KR20110010783A - Aryl ketone as mri - Google Patents

Abstract

상기 식에서,
R¹ 및 R²는 본원에 기재된 바와 같다.
특히, 본 발명의 화합물은 모노아민 재흡수 억제와 관련된 질병의 치료에 유용하다.The present invention relates to aryl pyrrolidinyl and piperidinyl ketone compounds of formula (I) or pharmaceutically acceptable salts and esters thereof, and methods of use thereof:
Formula I

Where
R ¹ and R ² are as described herein.
In particular, the compounds of the present invention are useful for the treatment of diseases associated with monoamine reuptake inhibition.

Description

Aryl ketone as MRI {ARYL KETONE AS MRI}

The present invention relates to aryl pyrrolidinyl and piperidinyl ketone compounds, and methods of use thereof. In particular, the compounds of the present invention are useful for the treatment of diseases associated with monoamine reuptake inhibition.

Monoamine deficiency has long been associated with depression, anxiety and other disorders (see, eg, Charney et al., J. Clin . Psychiatry ( 1998) 59, 1-14, Delgado et al., J.) . Clin . Psychiatry ( 2000) 67, 7-11, Resser et al., Depress.Anxiety ( 2000) 12 (Suppl 1) 2-19 and Hischfeld et al., J. Clin . Psychiatry ( 2000) 61 , 4-6]. In particular, serotonin (5-hydroxytryptamine) and norepinephrine are recognized as important regulatory neurotransmitters that play an important role in mood regulation. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, setraline, paroxetine, fluvoxamine, citalopram and ecitalopram have been provided as therapeutics for depression disorders (Masand et al., Harv) . . Rev. Psychiatry (1999) 7 , 69-84]). Noradrenaline or norepinephrine reuptake inhibitors such as reboxetine, atomoxetine, desipramine and nortriptyline have been provided as effective therapeutics for depression, attention deficit and hyperactivity disorders (Scates et al. , Ann . Pharmacother. ( 2000) 34, 1302-1312 and Tatsumi et al., Eur . J. Pharmacol. ( 1997) 340, 249-258).

Enhancement of serotonin and norepinephrine neurotransmission is recognized as synergistic in pharmacotherapy of depression and anxiety disorders, compared to improving only one of serotonin or norepinephrine neurotransmission (Thase et al., Br . J. Psychiatry ( 2001) 178, 234, 241 and Tran et al., J. Clin . Psychopharmacology ( 2003) 23, 78-86). Double reuptake inhibitors of both serotonin and norepinephrine, such as duloxetine, milnacipran and venlafaxine, are currently under development for the treatment of depression and anxiety disorders (Mallinckrodt et al., J. Clin . Psychiatry ( 2003). ) 5 (1) 19-28 and Bymaster et al., Expert Opin . Investig . Drugs ( 2003) 12 (4) 531-543]. In addition, dual reuptake inhibitors of serotonin and norepinephrine are schizophrenia and other psychosis, dyskinesia, drug addiction, cognitive impairment, Alzheimer's disease, compulsive behavior, attention deficit disorder, panic attack, social phobia, eating disorders, for example obesity And nervous system damage resulting from anorexia, bulimia and binge eating, stress, hyperglycemia, hyperlipidemia, non-insulin dependent diabetes, seizure disorders such as epilepsy, and stroke, brain trauma, brain infarction, head injury and bleeding Provide treatment for related conditions. In addition, dual reuptake inhibitors of serotonin and norepinephrine provide potential treatment for urinary tract disorders and disease states, and pain and inflammation.

More recently, "triple reuptake" inhibitors ("wide-range antidepressants" that inhibit reuptake of norepinephrine, serotonin and dopamine) have been recognized as useful for the treatment of depression and other central nervous system (CNS) signs ( Beer et al., J. Clinical Pharmacology ( 2004) 44: 1360-1367 and Skolnick et al., Eur J Pharmacol . ( 2003) Feb 14; 461 (2-3): 99-104.

Monoamine reuptake inhibitors also have utility in treating pain. Serotonin has been found to play a role in pain progression in the peripheral nervous system and contribute to peripheral sensitization and hyperalgesia in inflammation and nerve damage (Sommer et al., Molecular Neutrobiology (2004) 30 (2), 117-125). ). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been shown to be effective in treating pain in animal models (Iyengar et al., J. Pharm . Exper . Therapeutics (2004), 311, 576-584).

Thus, it is effective as a serotonin reuptake inhibitor, a norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor and / or an effective double reuptake inhibitor of serotonin, norepinephrine and / or dopamine, or a triple reuptake inhibitor of norepinephrine, serotonin and dopamine. There is a need for compounds as well as methods of making the compounds and methods of using the compounds in the treatment of depression, anxiety, urogenital, pain and other disorders.

The present invention satisfies this need.

Unless otherwise stated, the following terms used herein, including the specification and claims, have the definitions given below. Note that the singular forms used in the specification and the appended claims include the plural unless the context clearly dictates otherwise.

"Agonist" refers to a compound that enhances the activity of another compound or receptor site.

"Alkyl" means a monovalent linear or branched saturated hydrocarbon residue consisting solely of carbon and hydrogen atoms having 1 to 12 carbon atoms. "Lower alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, ie C ₁ -C ₆ alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Branched alkyl" means isopropyl, isobutyl, tert-butyl.

"Alkoxy" means a moiety of the formula -OR wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy and the like.

"Alkylsulfonyl" means a moiety of the formula -SO ₂ -R 'wherein R' is alkyl as defined herein.

"Amino" means a moiety of the formula -NRR ', wherein R and R' are each independently hydrogen or alkyl as defined herein. Amino thus includes "alkylamino" (where one of R and R 'is alkyl and the other is hydrogen) and "dialkylamino, where R and R' are both alkyl.

An “antagonist” refers to a compound that reduces or interferes with the action of other compounds or receptor sites.

"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic, bicyclic or tricyclic aromatic ring. Aryl groups may be optionally substituted as defined herein. Examples of aryl moieties include optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenyl Sulfonyl, diphenylisopropylidedenyl, benzodioxanyl, benzodioxylyl, benzooxazinyl, benzooxazinonyl, benzopiperazinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedi Oxyphenyl, ethylenedioxyphenyl and the like, but are not limited thereto. Preferred aryls include optionally substituted phenyl and optionally substituted naphthyl.

"Cyanoalkyl" means a moiety of the formula -R'-R, wherein R 'is alkylene as defined herein and R "is cyano or nitrile.

"Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of a monocyclic or bicyclic ring. Cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino unless otherwise specified. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and partially unsaturated derivatives thereof, and the like.

The term “heteroaryl” is a monocyclic, 2 ring member of 5 to 12 ring atoms containing one, two or three ring heteroatoms selected from N, O and S and the remaining ring atoms being C at least one aromatic ring. By cyclic or tricyclic radicals it is understood that the point of attachment of the heteroaryl radicals is on the aromatic ring. Heteroaryl rings may be optionally substituted as defined herein. Examples of heteroaryl moieties include optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxdiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, pyran Nyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzo Oxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, furinyl, quinazolinyl, quinolininyl, Naphthyridinyl, putridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, and the like.

"Halo" and "halogen" which may be used interchangeably refer to substituent fluoro, chloro, bromo or iodo.

"Heterocyclyl" means a monovalent saturated moiety consisting of one to three rings and containing one, two, three or four heteroatoms (selected from nitrogen, oxygen and sulfur). Heterocyclyl rings may be optionally substituted as defined herein. Examples of heterocyclyl moieties include optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, Isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyldininyl, benzothiazolidinyl, benzoazolilidinyl, dihydrofuranyl, tetrahydrofuryl, dihydropyranyl, tetra Hydropyranyl, thiamopolyyl, thiamopolyylsulfoxide, thiamopolyylsulfone, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. However, it is not limited thereto. Preferred heterocyclyls include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl and pyrrolidinyl.

"Optionally substituted" means "aryl", "phenyl", "heteroaryl" (indolyl, such as indol-1-yl, indol-2-yl and indol-3-yl, 2,3-dihydro Indolyls such as 2,3-dihydroindol-1-yl, 2,3-dihydroindol-2-yl and 2,3-dihydroindol-3-yl, indazolyl such as indazole -1-yl, indazol-2-yl and indazol-3-yl, benzimidazolyl such as benzimidazol-1-yl and benzimidazol-2-yl, benzothiophenyl, for example Benzothiophen-2-yl and benzothiophen-3-yl, benzoxazol-2-yl, benzothiazol-2-yl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyra Alkyl, cycloalkyl, alkoxy, halo when used in the context of genyl, oxazolyl, thiazolyl, isoxazolyl, isozozolyl, imidazolyl, pyrazolyl and quinolinyl) or "heterocyclyl" , Haloalkyl, haloalkoxy, cyano, nitro, amino, mono- Kill-amino, di-alkylamino, hydroxyalkyl, benzyloxy, optionally substituted thiophenyl, an optionally substituted pyrazolyl, optionally substituted pyridinyl, morpholino-carbonyl, - (CH _{2) q} -S (O) _r R ^f ,-(CH ₂ ) _q -NR ^g R ^h ,-(CH ₂ ) _q -C (= 0) -NR ^g R ^h ,-(CH ₂ ) _q -C (= 0)- C (= 0) -NR ^g R ^h ,-(CH ₂ ) _q -SO ₂ -NR ^g R ^h ,-(CH ₂ ) _q -N (R ^f ) -C (= 0) -R ⁱ ,-( CH ₂ ) _q -C (= 0) -R ⁱ , and-(CH ₂ ) _q -N (R ^f ) -SO ₂ -R ^g , wherein q is 0 or 1, r is 0 to 2, R ^f , R ^g and R ^h are each independently hydrogen or alkyl, and each R ⁱ is independently hydrogen, alkyl, hydroxy or alkoxy) 1 to 4 substituents selected from the group consisting of Aryl, phenyl, heteroaryl, or heterocyclyl independently substituted with four or two substituents. Some preferred optional substituents for "aryl", "phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl do. More preferred substituents are methyl, fluoro, chloro, trifluoromethyl, methoxy, amino and methanesulfonyl.

"Leaving group" means a group having a meaning commonly associated with synthetic organic chemistry, i.e., an atom or group which may be substituted under substitution reaction conditions. Examples of leaving groups are halogen, alkane- or arylenesulfonyloxy, for example methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy and thienyloxy, dihalophosphinoyloxy , Optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

"Modulator" means a molecule that interacts with a target. Interactions include, but are not limited to, agents, antagonists, and the like as defined herein.

“Optional” or “optionally” means that an event or situation described subsequently may occur, but does not necessarily occur, and the description includes when an event or situation occurs and when it does not occur.

"Disease" and "disease state" mean any disease, condition, symptom, disorder or sign.

"Inert organic solvent" or "inert solvent" is, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl Means that the solvent is inert under the reaction conditions described with respect to the solvent, including ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvent used in the reaction of the present invention is an inert solvent.

The term "pharmaceutically acceptable" is generally useful for the preparation of pharmaceutical compositions that are stable, nontoxic, biologically or otherwise undesirable, and mean veterinary acceptable as well as human pharmaceutical use.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable as defined herein and has the desired pharmacological activity of the parent compound. Such salts are inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, for example acetic acid, benzenesulfonic acid, benzoic acid, camposulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, Gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid Acid addition salts formed with succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; Or salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions, or coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, trometamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Preferred pharmaceutically acceptable salts are salts formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium. All references to pharmaceutically acceptable salts should be understood to include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein of the same acid addition salt.

"Protecting group" or "protecting group" is the meaning commonly associated with it in synthetic chemistry, which selectively blocks one reaction site in a multifunctional compound so that the chemical reaction can be carried out selectively at another unprotected reaction site. Means a flag. Particular methods of this invention rely on protecting groups that block reactive nitrogen and / or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to organic groups intended to protect nitrogen atoms against undesirable reactions during the synthesis process. Examples of nitrogen protecting groups include trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert- Butoxycarbonyl (BOC) and the like, but are not limited thereto. The skilled person will know how to select a group for its ease of removal and its ability to withstand subsequent reactions.

"Solvate" means a solvent addition form containing a stoichiometric or non stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state and thus form solvates. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water maintains its molecular state as H ₂ O therein, and the combination may form one or more hydrates.

"Subject" means mammal or non-mammal. Mammals are humans; Nonhuman primates such as chimpanzees and other apes and monkey species; Farm animals such as cattle, horses, sheep, goats, and swine; Domestic animals such as rabbits, dogs, and cats; Means a member of any mammal, including, but not limited to, laboratory animals including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to birds and the like. The term "subject" does not indicate a particular age or gender.

A “disease state” associated with serotonin, norepinephrine and / or dopamine neurotransmission is not only depressive and anxiety disorders but also schizophrenia and other psychosis, dyskinesia, drug addiction, cognitive disorders, Alzheimer's disease, attention deficit disorders such as ADHD, Compulsive behavior, panic attacks, social phobias, eating disorders such as obesity, anorexia, bulimia and binge eating, stress, hyperglycemia, hyperlipidemia, non-insulin dependent diabetes mellitus, seizure disorders such as epilepsy, and stroke, brain trauma, brain infarction , Treatment of conditions associated with nervous system damage resulting from head injury and bleeding, and disorders and disease states of the urinary tract. In addition, “disease states” associated with serotonin, norepinephrine and / or dopamine neurotransmission include the inflammatory state of a subject. The compounds of the present invention are useful for treating arthritis, including but not limited to rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus and pediatric arthritis, osteoarthritis, gouty arthritis and other arthritis conditions.

As used herein, the term “depression” refers to a major state of depression, prolonged depression, mood swings, sadness, despair, discouragement, darkness, gloom, depressed self-esteem, guilty feelings, and self-parallel from depressed mood, interpersonal contact Withdrawal, and physical signs, such as but not limited to eating disorders and sleep disorders.

As used herein, the term “anxiety” refers to an unpleasant or unpleasant emotional state associated with a psychophysiological response to an unrealistic, imagined or exaggerated risk or expectation of damage, and physical contingencies, such as increased heart rate, altered Respiratory rate, sweating, tremor, weakness and fatigue, feelings of impending danger, lethargy, worry and tension.

"Pain" means a somewhat local sense of discomfort, difficulty or pain resulting from stimulation of differentiated nerve endings. There are a number of types, including but not limited to blunt pain, phantom pain, tingling pain, acute pain, inflammatory pain, neuropathic pain, complex local pain, neuralgia, neuropathy, etc. ( Dorland's Illustrated Medical Dictionary , 28 ^th Edition, WB Saunders Company, Philadelphia, PA]). The purpose of pain treatment is to reduce the severity of pain perceived by the subject being treated.

"Neuropathic pain" means pain resulting from functional disorders and / or pathological changes as well as non-inflammatory lesions in the peripheral nervous system. Examples of neuropathic pain include, but are not limited to, heat or mechanical hyperalgesia, heat or mechanical allodynia, diabetes pain, captive pain, and the like.

A "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to treat that disease state. A "therapeutically effective amount" depends on the compound, the disease state to be treated, the severity or the treated disease, age and relative health of the subject, the route and form of administration, the judgment of the practitioner or veterinarian, and other factors.

“Defined above” and “as defined herein” incorporate by reference the broader definitions of the variables as well as the preferred, more preferred and most preferred definitions when present.

By "treating" or "treating" a disease state, (i) preventing the disease state, i.e., the clinical symptoms of the disease state may be exposed to or susceptible to the disease state, To prevent the development of a subject not represented; (ii) inhibiting the disease state, ie, arresting the onset of the disease state or clinical symptoms thereof; Or (iii) alleviation of the disease state, ie causing a temporary or permanent degeneration of the disease state or clinical symptoms thereof.

When “treating”, “contacting” and “reacting” refers to a chemical reaction, it is meant to add or mix two or more reactants under appropriate conditions to represent and / or produce the desired product. It should be appreciated that the reactions that represent and / or produce the desired product need not be generated directly from the combination of the two reactants that were initially added (ie, exhibit and / or ultimately lead to the formation of the desired product). One or more intermediates may be present in the mixture).

In general, the nomenclature used herein is based on the AUTONOM v.4.0, Bylestein Institute computerized system for generation of IUPAC strains. The chemical structures shown herein were made using ISIS® version 2.2. Any open valency shown on carbon, oxygen or nitrogen atoms in the structural formulas herein indicates the presence of hydrogen atoms.

Where chiral carbon is present in the chemical formula, it is intended that all stereoisomers associated with the chiral carbon be included in the formula.

All patents and publications presented herein are hereby incorporated by reference in their entirety.

One embodiment of the present invention provides a compound of formula I:

[Formula I]

Where

R ¹ is 4-chloro-3-methyl-phenyl;

2-amino-3,4-dichloro-phenyl;

3,4-dichloro-phenyl;

4-chloro-3- (3,3-dimethyl-butoxy) -phenyl;

3-benzyloxy-4-chloro-phenyl;

7-fluoro-1 H -indol-5-yl;

4-amino-3-chloro-5-trifluoromethyl-phenyl;

4-chloro-3- (4-fluoro-phenoxy) -phenyl;

4-chloro-3- (2-fluoro-phenoxy) -phenyl;

3-benzyloxy-4-chloro-phenyl;

4-chloro-3- (3,3-dimethyl-butoxy) -phenyl;

4-chloro-2-phenoxy-phenyl;

4-chloro-3- (tetrahydro-pyran-4-ylmethoxy) -phenyl;

4-chloro-3-trifluoromethoxy-phenyl;

4-chloro-3-phenylsulfanyl-phenyl;

3-benzenesulfonyl-4-chloro-phenyl;

4-chloro-3- (2-fluoro-phenoxy) -phenyl;

4-chloro-3- (4-fluoro-phenoxy) -phenyl;

4-chloro-3-phenoxy-phenyl;

4-bromo-3-phenoxy-phenyl;

4-amino-3-chloro-5-fluoro-phenyl;

4-amino-3-chloro-phenyl;

4-chloro-3- (4-trifluoromethyl-phenoxy) -phenyl;

3-chloro-4-methyl-phenyl;

Naphthalen-2-yl;

4-chloro-2-phenoxy-phenyl;

Phenyl;

3-chloro-4-methylamino-phenyl;

4-chloro-3-phenoxy-phenyl;

4-chloro-3- ( 2H -pyrazol-3-yl) -phenyl;

4-chloro-3- (methyl-phenyl-amino) -phenyl;

1 H -indol-5-yl;

4-chloro-3-pyridin-3-yl-phenyl;

3-bromo-4-imidazol-1-yl-phenyl; or

4-chloro-3-imidazol-1-yl-phenyl;

R ² is 3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;

(R) -3-isobutyl-pyrrolidin-3-yl;

(1R, 2S, 4S) -2-Butyl-7-aza-bicyclo [2.2.1] hept-2-yl;

3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl;

3-propyl-pyrrolidin-3-yl;

3-isobutyl-pyrrolidin-3-yl;

3-ethyl-pyrrolidin-3-yl;

(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl;

(S) -3- (3-methyl-butyl) -pyrrolidin-3-yl;

(S) -3-isobutyl-pyrrolidin-3-yl;

(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;

(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;

(S) -3-propyl-pyrrolidin-3-yl;

(R) -3-propyl-pyrrolidin-3-yl;

(R) -2-propyl-pyrrolidin-2-yl) -methanone;

4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl;

4-isobutyl-piperidin-4-yl;

4-propyl-piperidin-4-yl;

4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl;

4- (3-methyl-butyl) -piperidin-4-yl;

4-cyclopentylmethyl-piperidin-4-yl;

4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl;

4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl;

4- (3,4-Dichloro-benzyl) -piperidin-4-yl;

(1R, 2S, 5R) -2-Isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl;

(1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl;

(1R, 2S, 5R) -2-Ethyl-8-aza-bicyclo [3.2.1] oct-2-yl;

3-propyl-piperidin-3-yl;

(1R, 2R, 5R) -2-propyl-8-aza-bicyclo [3.2.1] oct-2-yl;

(1R, 2R, 5R) -2-Ethyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl;

(1R, 2R, 5R) -2-Butyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl;

3- (3,3-dimethyl-butyl) -piperidin-3-yl;

(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl; or

(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;

The compound is selected from the group consisting of the following compounds:

(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

((1R, 2S, 4S) -2-Butyl-7-aza-bicyclo [2.2.1] hept-2-yl)-(3,4-dichloro-phenyl) -methanone;

[4-Chloro-3- (3,3-dimethyl-butoxy) -phenyl]-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(3-benzyloxy-4-chloro-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-trifluoromethyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-[3- (3, 3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(3-benzyloxy-4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (3,3-dimethyl-butoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-chloro-2-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (tetrahydro-pyran-4-ylmethoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenylsulfanyl-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(3-benzenesulfonyl-4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-chloro-3-phenoxy-phenyl)-(3-ethyl-pyrrolidin-3-yl) -methanone;

(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (4-trifluoromethyl-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;

(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;

(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;

(4-Chloro-2-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;

[4- (3,4-Dichloro-benzyl) -piperidin-4-yl] -phenyl-methanone;

(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;

[4-Chloro-3- (methyl-phenyl-amino) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;

( 1H -Indol-5-yl)-((1R, 2R, 5R) -2-propyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

((1R, 2R, 5R) -2-butyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl)-(3,4-dichloro-phenyl) -methanone;

(4-Chloro-3-pyridin-3-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;

(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;

(3-bromo-4-imidazol-1-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;

(4-chloro-3-imidazol-1-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;

(3,4-Dichloro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone; And

(3,4-Dichloro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone.

Another aspect of the invention provides compound (s) selected from the group consisting of the following compounds:

(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;

(4-chloro-2-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-chloro-3-phenoxy-phenyl)-(3-ethyl-pyrrolidin-3-yl) -methanone;

(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;

(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;

(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;

(4-Chloro-2-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;

(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;

(3,4-Dichloro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone; And

(3,4-Dichloro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone.

Another aspect of the invention provides compound (s) selected from the group consisting of the following compounds:

(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;

(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;

(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;

(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;

[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone; And

(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone.

Another aspect of the invention provides compound (s) selected from the group consisting of the following compounds:

(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;

(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;

(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;

(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;

(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;

(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;

(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone; And

[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone.

Compounds of the invention can be prepared by a variety of methods shown in the exemplary synthetic schemes shown and described below.

Starting materials and reactants used in the preparation of such compounds are generally available from commercial suppliers, for example from Aldrich Chemical Co.Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15,Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals;Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40, according to the procedures described in the references. The following synthetic schemes are merely illustrative of some of the reactions in which compounds of the present invention may be synthesized, and various modifications may be made to such schemes and are suggested to those skilled in the art with reference to the disclosure contained herein.

Starting materials and intermediates in the synthesis scheme can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like, if desired. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein are preferably from about −78 ° C. to about 150 ° C., more preferably from about 0 ° C. to about 125 ° C., most preferably and typically about room temperature (or ambient temperature), eg For example, it is carried out in an inert atmosphere at atmospheric pressure in the reaction temperature range of about 20 ℃.

Scheme A, wherein X is a halo or other leaving group, may in each case be the same or different, PG is a protecting group, and m, n, Ar and R ¹ are compounds of the invention as defined herein One synthetic procedure available for preparation is illustrated.

[Reaction Scheme A]

In step 1 of Scheme A, an aryl compound a , such as an aryl halide, is reacted with an N-protected heterocyclic amide compound b in the presence of a strong base such as an alkyl lithium reagent to yield an aryl heterocyclic ketone c . The values of m and n of compound b can be selected to provide pyrrolidinyl, piperidinyl, azetidinyl, azefinyl, or similar heterocyclic moieties. In step 2, aryl heterocyclic ketone c is reacted with alkylating agent d to effect alkylation to afford compound e . Alkylating agents d may include, for example, benzyl halides, alkenyl halides or other alkylation reagents. Compound e can then be deprotected in step 3 to afford compound f which is a compound of formula I according to the invention.

Many variations on the Scheme A procedure are possible and will be readily apparent to those skilled in the art. For example, N-alkylation of compound f can provide compounds in which R ² is alkyl. If the R ¹ group introduced in step 2 is alkenyl or alkynyl, the hydrogenation reaction may be carried out to change R ¹ to alkyl.

Scheme B depicts another synthetic route to a compound of the invention wherein R is lower alkyl, PG is a protecting group, and m, n, Ar and R ¹ are defined herein.

[Scheme B]

In step 1 of Scheme B, the cyclic amine carboxylic acid ester g is treated with an alkylating agent h in the presence of a strong base such as an alkyl lithium reagent to give an alkylated cyclic amine I. The cyclic amine g may be pyrrolidinyl, piperidinyl, azetidinyl, azepinyl and the like depending on the values of m and n described above. In step 2, the ester group of compound j is reduced to yield primary alcohol compound j . Reduction of step 2 can be accomplished, for example, using LiAlH ₄ . The alcohol compound j is then partially oxidized in step 4 to give the aldehyde compound k . The oxidation of step 3 can be carried out, for example, using Dess Martin Periodinane or chromate reagents. In step 4, aldehyde compound k is reacted with aryl magnesium bromide m to effect alkylation to yield aryl alcohol compound n . In step 5 alcohol n is oxidized to the corresponding aryl ketone compound e . Oxidation can be performed using, for example, MnO ₂ , Swern's reagent or similar oxidant. In step 6 the aryl ketone compound e is deprotected to give compound f which is a compound of formula I according to the invention.

Many variations on Scheme B procedures are possible and are considered to be within the scope of the present invention. For example, aryl lithium reagents can be used in step 4. Specific details for the preparation of the compounds of the present invention are described in the Examples section below.

The compounds of the present invention can be used for the inhibition of monoamine reuptake, in particular for the treatment of diseases or conditions associated with serotonin neurotransmission, norepinephrine neurotransmission and / or dopamine neurotransmission. These diseases and conditions include depression and anxiety disorders, as well as schizophrenia and other psychosis, dyskinesia, drug addiction, cognitive impairment, Alzheimer's disease, attention deficit disorders such as ADHD, compulsive behavior, panic attacks, social fear, eating disorders, For example obesity, anorexia, bulimia and bulimia, stress, hyperglycemia, hyperlipidemia, non-insulin dependent diabetes mellitus, seizure disorders such as epilepsy, and neurological damage associated with stroke, brain trauma, brain infarction, head injury and bleeding Treatment of the condition.

In addition, the compounds of the present invention can be used to treat disorders and disease states of the urinary tract, such as stress urinary incontinence, urinary incontinence, benign prostatic hyperplasia (BPH), prostatitis, detrusor hyperreflexion, exit obstruction, urinary obstruction, enuresis, urgency, irritable bladder, hypersensitivity It can be used to treat pelvis, urethritis, prostate pain, cystitis, idiopathic bladder hypersensitivity.

In addition, the compounds of the present invention have anti-inflammatory and / or analgesic in vivo, and thus include, but are not limited to, neuropathic pain, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain due to burns. , Migraine or cluster headaches, nerve damage, neuritis, neuralgia, poisoning, ischemic damage, interstitial cystitis, cancer pain, virus, parasite or bacterial infections, post-traumatic injury (including fractures and sports injuries), and functional intestines Usefulness is expected to be found in the treatment of disorders, eg, disease states associated with pain conditions from various causes, including pain associated with irritable bowel syndrome.

In addition, the compounds of the present invention are useful in the treatment of arthritis including but not limited to rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus and pediatric arthritis, osteoarthritis, gouty arthritis and other arthritis conditions.

As mentioned above, the novel compounds of the present invention and their pharmaceutically usable salts and esters have beneficial pharmacological properties. Therefore, the compounds of the present invention may be used alone or in combination with other drugs for the treatment and prevention of diseases associated with monoamine reuptake inhibition. These diseases include but are not limited to depression and / or anxiety.

Therefore, the present invention also relates to pharmaceutical compositions comprising a compound as defined herein above and a pharmaceutically acceptable carrier and / or adjuvant.

Similarly, the present invention includes the aforementioned compounds for use as therapeutically active substances, in particular for the treatment or prevention of diseases associated with monoamine reuptake inhibition, in particular as therapeutically active substances for the treatment or prevention of depression and / or anxiety.

In another preferred embodiment, the invention relates to a method for the treatment or prevention of diseases associated with monoamine reuptake inhibition, in particular for the treatment or prevention of depression and / or anxiety, comprising administering a compound as defined above to a human or animal. will be.

The invention also encompasses the use of the compounds as defined above for the treatment or prevention of diseases associated with monoamine reuptake inhibition, in particular for the treatment or prevention of depression and / or anxiety.

The present invention also relates to the use of the aforementioned compounds for the treatment or prevention of diseases associated with monoamine reuptake inhibition, in particular for the preparation of a medicament for the treatment or prevention of depression and / or anxiety.

Representative compounds according to the method of the present invention are shown in Table 1 below with mass spectral (M + 1) values and pIC ₅₀ for SERT, NET and DAT, respectively:

TABLE 1

The present invention relates to a racemic or non-racemic mixture of one or more compounds of the present invention, or individual isomers, ideal forms thereof, or one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic components. And pharmaceutical compositions comprising an acceptable salt or solvate.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any acceptable mode of administration for drugs that provide similar utility. Suitable dosage ranges are typically dependent on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, the indications to which the administration is directed, and the preferences and experience of the associated specialist. 1 to 500 mg daily, preferably 1 to 100 mg daily, and most preferably 1 to 30 mg daily. One skilled in the art of disease treatment can, without undue experimentation, rely on personal knowledge and the disclosure herein to identify a therapeutically effective amount of a compound of the invention for a given disease.

Compounds of the invention are suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intramedullary, subcutaneous and intravenous) administration or inhalation or It may be administered as a pharmaceutical formulation including a form suitable for administration by aeration. Preferred modes of administration are generally oral using a convenient daily dosage regimen that can be adjusted to the extent of pain.

The compounds of the present invention may be in pharmaceutical composition and unit dosage form with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, wherein the unit dosage forms are any amount to the same as the intended daily dosage range used It may contain a suitable effective amount of the active ingredient. The pharmaceutical composition may be solid, for example as a tablet or filled capsule, semisolid, powder, sustained release formulation, or liquid, for example as a solution, suspension, emulsion, elixir, or oral filled capsule; Or rectal or vaginal administration in the form of suppositories; Or in the form of sterile injectable solutions for parenteral use. Accordingly, formulations containing about 1 mg of active ingredient per tablet, more broadly about 0.01 to about 100 mg of active ingredient, are suitable representative unit dosage forms.

The compounds of the present invention can be formulated in a variety of oral dosage forms. Pharmaceutical compositions and dosage forms comprise a compound of the present invention or a pharmaceutically acceptable salt thereof as the active ingredient. Pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that can act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. In powders, the carrier is generally a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Preferably, the powders and tablets contain about 1% to about 70% active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter, and the like. It doesn't work. The term “formulation” includes formulations of the active compounds with encapsulating material as carriers, providing a capsule in which the active ingredient is surrounded by a carrier associated with or without a carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in solution, for example an aqueous propylene glycol solution, or may contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water together with viscous materials such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

Compounds of the invention may be formulated for parenteral administration (eg, injection, eg, bolus injection or continuous infusion) and are multi-administered with ampoules, pre-filled syringes, small infusions or added preservatives. It may be present as a unit dosage form of the container. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous excipients, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), and injectable organic esters (e.g. ethyl oleate), preservatives, wetting agents, emulsifiers Or formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by preservative isolation of sterile solid or by lyophilization from solution to consist of suitable excipients such as sterile, pyrogen-free water before use.

The compounds of the present invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. The lotion may be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents. Formulations suitable for topical administration to the oral cavity include lozenges comprising the active substance in an aromatic base, generally sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. Low melt waxes, such as mixtures of fatty acid glycerides or cocoa butter, are first melted and homogeneously dispersed by, for example, stirring the active ingredient. The molten homogeneous mixture is then poured into a mold of convenient size, cooled and solidified.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing carriers known in the art as appropriate in addition to the active ingredient are known to be suitable in the art.

The compounds of the present invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example using a dropper, pipette or sprayer. The formulations may be provided in single or multiple dosage forms. In the latter dropper or pipette, this may be achieved by administering to the patient any suitable volume of solution or suspension. In the case of spraying, this can be achieved for example using a metering spray pump.

The compounds of the invention may be formulated for aerosol administration, including intranasal administration, in particular. In general, the compounds have a small particle size of for example 5 μm or less. The particle size can be obtained by means known in the art such as, for example, micronization. The active ingredient is pressurized packing with a suitable propellant such as chlorofluorocarbon (CFC) (e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), or carbon dioxide or other suitable gas. It is provided. Aerosols may also conveniently contain surfactants such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredient may be provided in the form of a dry powder such as a powdered mixture of compounds in suitable powder bases such as lactose, starch, starch derivatives, for example hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). have. The powder carrier forms a gel in the nasal cavity. The powder composition is present in unit dosage form, such as a capsule or cartridge or blister pack of gelatin, into which the powder can be administered by inhaler.

If desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in a transdermal or subcutaneous drug delivery device. Such delivery systems are advantageous when the sustained release of the compound is required and when the patient's compliance with the treatment regimen is important. Compounds in transdermal delivery systems are often attached to skin-adhesive solid supports. In addition, the compound may be combined with a penetration enhancer, such as azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subcutaneous implants encapsulate the compound in a fat soluble membrane, such as silicone rubber, or a biodegradable polymer (eg, polylactic acid).

The pharmaceutical preparations are preferably in unit dosage form. In such forms, the formulation is subdivided into unit dosages containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation wherein the package contains discrete amounts of the preparation, such as packaged tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or may have the appropriate number of formulations in any package form.

Other suitable pharmaceutical carriers and formulations thereof are described in Remington , The Science and Practice of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described in the Examples below.

Example

The following Preparation Examples and Examples are provided to enable those skilled in the art to more clearly understand the present invention and to practice the present invention. It is merely illustrative and representative of the invention and should not be taken as limiting the scope of the invention.

The following abbreviations may be used in the examples:

AcOH acetic acid

Bn benzyl

(BOC) ₂ O di-tert-butyl dicarbonate

t-BuLi tert-butyllithium

t-BuOH tert-butyl alcohol

m-CPBA 3-chloroperoxybenzoic acid

DCM dichloromethane / methylene chloride

DEA diethylamine

DIPEA diisopropylethylamine

DIBALH diisobutylaluminum hydride

DMF N, N-dimethylformamide

DMP Dess Martin Periodinan (1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one)

Dppf 1,1'-bis (diphenylphosphino) ferrocene

EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

HPLC high pressure liquid chromatography

HOBt 1-hydroxybenzotriazole

LAH Lithium Aluminum Hydride

LHMDS lithium bis (trimethylsilyl) amide

MeOH Methanol

MsCl Methanesulfonyl Chloride

NBS N-bromosuccinimide

PFBSF perfluorobutanesulfonyl fluoride

TBAF Tetrabutylammonium Fluoride

TBAHS Tetrabutyl Ammonium Hydrogen Sulfate

TBDMS tert-butyldimethylsilyl

TMSI iodotrimethylsilane

TEA triethylamine

TIPS triisopropylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TMAF Tetramethylammonium Fluoride

TMS trimethylsilyl

Preparation Example 1

5- Bromo -One- Triisopropylsilane -1H-indole

Lithium bis (trimethylsilyl) amide (1.0M in THF, 28 mL, 28 mmol) was slowly added to a solution of 5-bromoindole (5.00 g, 25.5 mmol) in THF (60 mL) under nitrogen atmosphere at -78 ° C. Added. The reaction mixture was stirred at −78 ° C. for 20 minutes, then triisopropylsilylchloride (5.7 mL, 26.8 mmol) was added. The resulting mixture was stirred at −78 ° C. for 20 minutes and then warmed to room temperature over 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl, diluted with water and the resulting mixture was extracted with EtOAc. Separate organic layer, MgSO ₄ Dried over, filtered and evaporated under reduced pressure to afford the crude oil, which was purified by flash chromatography (hexane 100%) to 8.94 g (99% yield) of 5-bromo-1-triisopropylsilaneyl-. 1 H -indole was obtained as a colorless oil.

In a similar manner, using the appropriate starting materials, the following compounds were prepared:

5-bromo-1-triisopropylsilanyl-1 H -indazole (86% yield, yellow solid);

5-bromo-1-triisopropylsilanyl-1 H -pyrrolo [2,3- b ] pyridine (87% yield, yellow solid);

5-bromo-2-methyl-1-triisopropylsilylyl-1 H -indole;

5-bromo-1-triisopropylsilanyl-2,3-dihydro-1 H -indole (100% yield, white solid);

5-bromo-1- ( tert -butyl-dimethyl- silanyl ) -1 H -indole; And

5-bromo-7-fluoro-1-triisopropylsilylyl-1 H -indole.

Production Example 2

( R ) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -Butyl ester 2-methyl ester

Synthesis of ( R ) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester was carried out according to the process shown in Scheme C.

Scheme C

Step 1: (R) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -Butyl ester

A mixture of (R) -2-benzyl-pyrrolidine-2-carboxylic acid (2.07 g, 10.1 mmol) and tetramethylammonium hydroxide pentahydrate (1.83 g, 10.1 mmol) in acetonitrile (100 mL) under nitrogen After stirring for 90 minutes, (Boc) ₂ O (3.31 g, 15.2 mmol) was added. After 48 h a second fraction of (Boc) ₂ O (1.10 g, 5.0 mmol) was added. After 24 hours the reaction mixture was concentrated in vacuo and then partitioned between ether (100 mL) and water (50 mL). The aqueous phase was washed with ether (50 mL) and then acidified to pH 4 with 10% aqueous citric acid (20 mL). The resulting solution was extracted with EtOAc and the combined extracts were washed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to (R) -2-benzyl-pyrrolidine-1,2- Dicarboxylic acid 1- tert -butyl ester (1.26 g, 4.13 mmol, 41%) was obtained as foam.

Step 2: (R) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -Butyl ester 2-methyl ester

Agitation of (R) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester (1.23 g, 4.0 mmol) in THF (10 mL) and methanol (10 mL) at 0 ° C. under nitrogen. To the prepared solution was added dropwise TMS-diazomethane (2.0M solution in 5.0 mL of hexane, 5.0 mmol). The reaction mixture was allowed to warm to ambient temperature and then concentrated in vacuo to oil (1.36 g). Purification by chromatography (silica, 5-15% EtOAc in hexanes) gave (R) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.03 g, 3.23 mmol , 81%) was obtained as an oil.

Production Example 3

2-Butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

Synthesis of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester was carried out according to the process shown in Scheme D.

Scheme D

Step 1: 2-N-butyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -Butyl ester 2-methyl ester

LHMDS (14.4 mL of 14.4 mL) in a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (3.00 g, 13.1 mmol) in THF (50 mL) at −78 ° C. and under nitrogen. 1.0M solution in THF, 14.4 mmol) was added dropwise. After 30 minutes, a solution of 1-iodobutane (2.23 mL, 19.7 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at −78 ° C., warmed to ambient temperature over 90 minutes, then quenched by addition of saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO ₃ and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil (4.5 g). Purification by chromatography (silica, 10% EtOAc in hexanes) to give 2-butyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (2.57 g, 9.01 mmol, 69%) Obtained as a colorless oil.

The following compounds were similarly prepared using the above procedure and appropriate starting materials:

2-propyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (colorless oil, 85%) (using 1-iodopropane);

2-ethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (colorless oil, 76%) (using chloromethoxy-ethane);

2- (3,3-Difluoro-allyl) -pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (colorless oil, 11%) (1,1,1-trifluoro Rho-3-iodopropane);

2-isopropoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-ethyl ester (colorless oil, 49%) (chloromethoxyisopropyl ether and pyrrolidine-1,2- Dicarboxylic acid 1- tert -butyl ester 2-ethyl ester);

2-isobutyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-ethyl ester (colorless oil, 67%) (1-iodo-2-methylpropane and pyrrolidine-1,2 Dicarboxylic acid 1- tert -butyl ester 2-ethyl ester);

2-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-ethyl ester (colorless oil, 50%) (cyclopropylmethyl bromide and pyrrolidine-1,2-dicarboxylic acid 1 from tert -butyl ester 2-ethyl ester);

5,5-dimethyl-2-propyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (colorless oil, 76%) (1-iodopropane and 5,5-di Methyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester);

(2R, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (colorless oil, 26 %) And (2S, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester colorless oil , 30%) (1-iodopropane and (2S, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2- Obtained from methyl ester);

2-propyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (colorless oil, 80%) of (1-iodo-propane, and azetidine-1,2-dicarboxylic acid 1-tert- Butyl ester 2-methyl ester);

2-propyl-piperidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-ethyl ester (colorless oil, 38%) (1-iodopropane and piperidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-ethyl ester); And

2- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.

Step 2: 2-N-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

LiAlH ₄ (0.842 g, 2.95 mmol) in a stirred solution of 2-butyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (0.842 g, 2.95 mmol) in THF (30 mL) under nitrogen at 0 ° C. 2.95 mL of 1.0M solution in THF, 2.95 mmol) was added dropwise. After 15 minutes the reaction mixture was quenched by addition of sodium sulfate decahydrate (2.5 g) and then filtered. The filter cake was washed with DCM (50 mL) and the combined filtrates were concentrated in vacuo to give 2-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.763 g) as a clear colorless oil. And used directly without further purification.

The following compounds were similarly prepared using the above procedure and appropriate starting materials:

2-hydroxymethyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow oil, 94%);

2-hydroxymethyl-2-isopropoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 89%);

2-hydroxymethyl-2-isobutyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 100%);

2-cyclopropylmethyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 100%);

2-hydroxymethyl-5,5-dimethyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 100%);

(2S, 4R) -2-hydroxymethyl-2-propyl-4- (1,1,2,2-tetramethyl-propoxy) -pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 100 %); And

2-hydroxymethyl-2- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert -butyl ester.

Step 3: 2-N-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

DMP (2.50) in a stirred solution of 2-2-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.763 g, about 2.95 mmol) in DCM (30 mL) at 0 ° C. under nitrogen. g, 5.90 mmol) was added in a single fraction, then the reaction mixture was allowed to warm to ambient temperature. After 14 hours the reaction mixture was diluted with DCM (70 mL) and washed with 1N NaOH (2 × 30 mL) and brine (30 mL), then dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by chromatography (silica, 10-20% EtOAc in hexanes) gave 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.359 g, 1.41 mmol, 48%) as pale yellow oil. Obtained.

The following compounds were similarly prepared using the above procedure and appropriate starting materials:

2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 92%);

2-formyl-2-isopropoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 77%);

2-formyl-2-isobutyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 79%);

2-cyclopropylmethyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow oil, 85%);

2-formyl-5,5-dimethyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 85%);

(2S, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 63%); And

2-formyl-2- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert -butyl ester.

Preparation Example 4

2-Ethoxymethyl-2-formyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

Synthetic procedures for this preparation are outlined in Scheme E below.

Scheme E

2-ethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1- tert -butyl ester 2-methyl ester (1.00 g, 3.48 mmol, Preparation Example 3 Step 1 in THF (40 mL) under nitrogen at −78 ° C. To a stirred solution of DIBALH (4.09 mL of PhCH ₃₎ so that the internal temperature does not exceed -75 ° C. 1.7M solution, 6.96 mmol) was added dropwise over 15 minutes. After 4.5 hours the reaction mixture was quenched by addition of sodium sulfate decahydrate (4 g) and MeOH (0.5 mL) and then warmed to ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc (200 mL) and the combined filtrates were concentrated in vacuo to a colorless oil. Purification by chromatography (silica, 10-30% EtOAc in hexanes) to give 2-ethoxymethyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.528 g, 2.05 mmol, 59%) as clear Obtained as a colorless oil.

The following compounds were similarly prepared using the above procedure and appropriate starting materials:

2- (3,3-Difluoro-allyl) -2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 100%);

(2R, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 36%);

2-formyl-2-propyl-azetidine-1-carboxylic acid tert -butyl ester (colorless oil, 53%); And

2-hydroxymethyl-2-propyl-piperidine-1-carboxylic acid tert -butyl ester (colorless oil, 72%).

Preparation Example 5

4-Formyl-4-propyl-piperidine-1-carboxylic acid tert -Butyl ester

Synthetic procedures for this preparation are outlined in Scheme F below.

Scheme F

Step 1: 4-propyl-piperidine-1,4- Dicarboxylic acid  One- tert -Butyl ester 4-ethyl ester

To a solution of potassium hexamethyldisilazide (29.1 g, 146 mmol) in THF (200 mL) at −78 ° C. was added ethyl N- Boc-piperidine-4-carboxylate (25 g, 97 mmol). The reaction mixture was stirred at −78 ° C. for 30 minutes, then 1-iodopropane (14.2 mL, 146 mmol) was added slowly. The reaction mixture was stirred for an additional 20 minutes at −78 ° C., then warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (0%-50% EtOAc in hexane) to give 19.3 g (66%) of 4-propyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester Was obtained as a yellow oil.

Step 2: 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-propyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (19.3 g, 64.3 mmol) in THF (120 mL) at 0 ° C. in lithium aluminum hydride (THF 1.0 M, 65 mL, 65 mmol) was added slowly. The reaction mixture was stirred at 0 ° C. for 1 hour, then quenched by the slow addition of solid Na ₂ SO ₄ .10H ₂ O and stirred vigorously at room temperature for 1 hour. The solid was removed by filtration through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a yellow oil.

In a separate flask, oxalyl chloride (5.4 mL, 64.3 mmol) was dissolved in dichloromethane (150 mL) and cooled to -78 ° C. Dimethylsulfoxide (9.1 mL, 130 mmol) was added slowly and the reaction mixture was stirred at -78 ° C for 15 min. The yellow oil dissolved in dichloromethane (50 mL) was added slowly. After stirring at −78 ° C. for 15 minutes, Et ₃ N (45 mL, 322 mmol) was added. The reaction mixture was allowed to warm to room temperature over 1 hour, then quenched with H ₂ O and extracted with dichloromethane. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% -50% EtOAc in hexanes) to give 12.3 g (75%) of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. Obtained.

Example 1

(3-benzyl-pyrrolidin-3-yl)-(1 H -Indol-5-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme G.

Scheme G

Step 1: 3- (methoxy-methyl-carbamoyl) -pyrrolidine-1-carboxylic acid tert -Butyl

Pyrrolidine-1,3-dicarboxylic acid 1- tert -butyl ester (3.00 g, 13.93 mmol), N, O-dimethylhydroxylamine hydrochloride (1.63 g, 16.72 mmol), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (2.94 g, 15.32 mmol) and 1-hydroxybenzotriazole (2.07 g, 15.32 mmol) were placed in a 100 mL round bottom flask and dissolved in DMF (30 mL). . Diisopropylethylamine (6.1 mL, 34.82 mmol) was added slowly and the reaction mixture was stirred at rt for 24 h. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, MgSO ₄ Dried over, filtered and evaporated under reduced pressure to give 2.60 g (72% yield) of 3- (methoxy-methyl-carbamoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester as a pale yellow oil. Used in the next step without further purification.

Similarly, the following compounds were prepared using the procedure of step 1:

4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert -butyl ester;

3- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert -butyl ester;

2- (methoxy-methyl-carbamoyl) -azetidine-1-carboxylic acid tert -butyl ester; And

3- (methoxy-methyl-carbamoyl) -azepine -1-carboxylic acid tert -butyl ester.

Step 2: 3- (1-triisopropylsilanyl-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Tert -butyllithium (1.7 M in pentane, 13 mL, 22.13 mmol) was added 5-bromo-1-triisopropylsilaneyl-1 H -indole (3.54 g) in THF (35 mL) under nitrogen atmosphere at -78 ° C. , 10.06 mmol). The pale yellow reaction mixture was stirred at −78 ° C. for 15 minutes, then 3- (methoxy-methyl-carbamoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (2.60 g, 10.06 in THF (5 mL) mmol) was added slowly. The resulting mixture was stirred at −78 ° C. for 30 minutes and then warmed to room temperature over 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl and partitioned between water and EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (10% -25% EtOAc in hexanes) to 2.66 g (56% yield) of 3- (1-triisopropylsilyl-1 H -indole-5-carbonyl) Pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a colorless oil.

Step 3: 3-benzyl-3- (1-triisopropylsilylyl-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Lithium bis (trimethylsilyl) amide (1.0 M in THF, 12.1 mL) under nitrogen atmosphere at 0 ° C. was added 3- (1-triisopropylsilylyl- 1H -indole-5-carbonyl in THF (25 mL) To a solution of) -pyrrolidine-1-carboxylic acid tert -butyl ester (1.90 g, 4.03 mmol). The reaction mixture was stirred for 10 min at 0 ° C., then benzyl bromide (1.9 mL, 16.12 mmol) was added. The resulting mixture was warmed to rt and stirred for 1.5 h. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl, then diluted with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% -20% EtOAc in hexanes) to 1.55 g (69% yield) of 3-benzyl-3- (1-triisopropylsilaneyl-1 H -indole-5- Carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a white foam.

Step 4: 3-benzyl-3- (1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

A solution of tetrabutylammonium fluoride (1.0 M in THF, 1.2 mL) at 0 ° C. was added with 3-benzyl-3- (1-triisopropylsilaneyl-1 H -indole-5-carbonyl in THF (15 mL). It was added slowly to a solution of) -pyrrolidine-1-carboxylic acid tert -butyl ester (670 mg, 1.19 mmol). The resulting light yellow mixture was stirred at 0 ° C. for 20 minutes and then quenched by addition of water. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with MgSO ₄ Dried over, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% -50% EtOAc in hexanes) to give 447 mg (93% yield) of 3-benzyl-3- (1 H -indole-5-carbonyl) -pyrrolidine- 1-carboxylic acid tert -butyl ester was obtained as a white foam.

Step 5: (+)-3-benzyl-3- (1 H -Indole-5- Carbonyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester and (-)-3-benzyl-3- (1 H -Indole-5- Carbonyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl s Separation

Two enantiomers of 3-benzyl-3- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester were subjected to chiral HPLC (using Chiralpak IA column, 90 /). 10 hexanes / EtOH, 1.4 mL / min).

Enantiomer A: [α] _D = + 8.6 ° (5.2 mg / 1.0 mL of EtOH).

Enantiomer B: [α] _D = -10.2 ° (5.2 mg / 1.0 mL of EtOH).

Step 6: (+)-(3-benzyl- Pyrrolidine -3- days)-(1 H -Indole-5-day)- Methanone  And (-)-(3-benzyl-p Lollidine -3- days)-(1 H -Indole-5-day)- Methanone

HCl solution (1.0M in MeOH, 12 mL) was added to 3-benzyl-3- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester enantiomer A in MeOH (5 mL). (257 mg, 0.635 mmol) was added to the solution. The resulting pale yellow solution was stirred at room temperature for 6 hours, then cooled to 0 ° C. and quenched by addition of aqueous NaOH (1.0 M). The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (5% -10% MeOH in DCM with 0.5% NH ₄ OH) to 179 mg (93% yield) of (3-benzyl-pyrrolidin-3-yl)- (1 H -indol-5-yl) -methanone was obtained, which was dissolved in a mixture of DCM / MeOH. HCl (1M in Et ₂ O) solution was added, the resulting mixture was evaporated under reduced pressure and the residue triturated with Et ₂ O to give 173 mg of (3-benzyl-pyrrolidin-3-yl)-(1 H -Indol-5-yl) -methanone hydrochloride enantiomer A was obtained as a white powder. MS = 305 [M + H] ⁺ ; [a] _D = -26.3 ° (5.40 mg / 1.0 mL of MeOH).

In a similar manner (3-benzyl-pyrrolidin-3-yl)-( 1H -indol-5-yl) -methanone hydrochloride enantiomer B was prepared: [α] _D = + 24.4 ° (5.45 mg /1.0 mL of MeOH).

Using the procedure of Example 1 with the appropriate starting material, the following compounds were prepared:

(3-benzyl-pyrrolidin-3-yl)-(7-fluoro-1 H -indol-5-yl) -methanone hydrochloride, pink powder, MS = 324 [M + H] ⁺ ;

( 1H -Indol-5-yl)-[3- (3-methoxy-benzyl) -pyrrolidin-3-yl] -methanone hydrochloride, pale pink powder, MS = 335 [M + H] ⁺ ;

3- [3- ( 1H -Indol-5-carbonyl) -pyrrolidin-3-ylmethyl] -benzonitrile hydrochloride, white solid, MS = 330 [M + H] ⁺ ;

[3- (3-Fluoro-benzyl) -pyrrolidin-3-yl]-( 1H -indol-5-yl) -methanone hydrochloride, pink-orange solid, MS = 323 [M + H] ⁺ ;

[3- (4-Fluoro-benzyl) -pyrrolidin-3-yl]-( 1H -indol-5-yl) -methanone hydrochloride, red powder, MS = 323 [M + H] ⁺ ;

( 1H -Indol-5-yl)-[3- (4-methoxy-benzyl) -pyrrolidin-3-yl] -methanone hydrochloride, MS = 335 [M + H] ⁺ ;

[3- (3,4-Dichloro-benzyl) -pyrrolidin-3-yl]-( 1H -indol-5-yl) -methanone hydrochloride, off-white powder, MS = 374 [M + H] ⁺ ;

[3- (2-Fluoro-benzyl) -pyrrolidin-3-yl]-( 1H -indol-5-yl) -methanone hydrochloride, pink solid, MS = 323 [M + H] ⁺ ;

(3-benzyl-pyrrolidin-3-yl)-(2-methyl-1 H -indol-5-yl) -methanone hydrochloride, yellow solid, MS = 319 [M + H] ⁺ ;

(3-benzyl-pyrrolidin-3-yl)-(2,3-dihydro-1 H -indol-5-yl) -methanone hydrochloride, light yellow powder, MS = 307 [M + H] ⁺ ;

(4-benzyl-piperidin-4-yl)-( 1H -indol-5-yl) -methanone, off-white powder, MS = 319 [M + H] ⁺ ;

(3-benzyl-piperidin-3-yl)-( 1H -indol-5-yl) -methanone, white solid, MS = 319 [M + H] ⁺ : two enantiomers were converted to chiralpak IB Separated by chiral HPLC on column (65/35 hexanes / EtOH + 0.1% DEA, 1.0 ml / min):

Enantiomer A Hydrochloride Salt (white powder), [α] _D = -126.4 ° (5.12 mg / 1.024 mL of MeOH),

Enantiomer B hydrochloride salt (white powder), [α] _D = + 129.4 ° (5.26 mg / 1.052 mL of MeOH);

( 1H -Indol-5-yl)-[3- (4-methoxy-benzyl) -piperidin-3-yl] -methanone hydrochloride, pale yellow powder, MS = 349 [M + H] ⁺ ;

[3- (3-Fluoro-benzyl) -piperidin-3-yl]-( 1H -indol-5-yl) -methanone hydrochloride, white solid, MS = 337 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 2

5- (3-benzyl-pyrrolidine-3-carbonyl) -1H-indole-3-carbonitrile

The synthesis procedure described in this example was carried out according to the process shown in Scheme H below.

Scheme H

Step 1: 3- (1-Benzenesulfonyl-3-iodo-1H-indole-5-carbonyl) -3-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Freshly ground potassium hydroxide (35 mg, 0.617 mmol) was added 3-benzyl-3- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester in DMF (1.5 mL). (100 mg, 0.247 mmol) was added to the solution. Then a solution of iodine (63 mg, 0.247 mmol) in DMF (0.5 mL) was added dropwise and the reaction mixture was stirred at rt for 45 min. The reaction was quenched by addition of aqueous Na ₂ S ₂ O ₃ solution and diluted with water. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was immediately dissolved in DMF (2 mL) and NaH (60% in inorganic oil, 12 mg, 0.296 mmol) was added to the solution. The resulting mixture was stirred for 20 minutes, after which benzenesulfonyl chloride (38 μL, 0.296 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then quenched by addition of water. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% -30% EtOAc in hexanes) to 150 mg (91% yield) of 3- (1-benzenesulfonyl-3-iodo-1H-indole-5-carbonyl ) -3-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a white foam.

Step 2: 3- (1-benzenesulfonyl-3-cyano-1 H -Indole-5-carbonyl) -3-benzyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

Copper (I) cyanide (76 mg, 0.852 mmol) was added 3- (1-benzenesulfonyl-3-iodo-1H-indole-5-carbonyl) -3-benzyl-pyrrolidine-1-carboxylic acid tert To a 25 mL round bottom flask filled with -butyl ester (143 mg, 0.213 mmol), followed by 1,1'-bis (diphenylphosphino) ferrocene (24 mg, 0.043 mmol) and tris (dibenzylideneacetone ) Dipalladium (0) (10 mg, 0.011 mmol) was added. 1,4-dioxane (1.5 mL) was then added and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc in hexanes) to 115 mg (95% yield) of 3- (1-benzenesulfonyl-3-cyano-1 H -indole-5-carbonyl)- 3-benzyl-pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a pale yellow foam.

Step 3: 3-benzyl-3- (3-cyano-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Water (1 mL) was added 3- (1-benzenesulfonyl-3-cyano-1 H -indole-5-carbonyl) -3-benzyl-pyrrolidine-1-carboxylic acid tert in MeOH (4 mL). To a solution of butyl ester (100 mg, 0.175 mmol) was added followed by potassium carbonate (73 mg, 0.525 mmol). The resulting mixture was extracted with DCM, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% -50% EtOAc in hexanes) to give 3-benzyl-3- (3-cyano-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a white foamy solid.

Step 4: 5- (3-benzyl- Pyrrolidine -3- Carbonyl )-One H Indole-3- Carbonitrile

HCl (1.0 M in MeOH, 8 mL) solution was added at 0 ° C. in 3-benzyl-3- (3-cyano-1 H -indole-5-carbonyl) -pyrrolidine-1- in MeOH (2 mL). To the solution of carboxylic acid tert -butyl ester (169 mg, 0.393 mmol) was added slowly. The resulting pale yellow mixture was stirred at rt for 4 h and then quenched by addition of 0 ° C. aqueous NaOH (1.0 M). The resulting mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude was purified by flash chromatography (MeOH in DCM with 0.5% NH ₄ OH) to 42 mg of 5- (3-benzyl-pyrrolidine-3-carbonyl) -1 H -indole-3-carbo Nitrile was obtained as a white foamy solid. This product was dissolved in DCM and HCl solution (1.0 M in Et ₂ O, 1 equiv) was added. MeOH was added and the resulting mixture was evaporated under reduced pressure. The residue was triturated with Et ₂ O to collect 32 mg of 5- (3-benzyl-pyrrolidine-3-carbonyl) -1 H -indole-3-carbonitrile hydrochloride as a white solid. MS = 330 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 3

(1H-indazol-5-yl)-(3-propyl-pyrrolidin-3-yl) -methanone hydrochloride

The synthesis procedure described in this example was carried out according to the process shown in Scheme I below.

Scheme I

Step 1: 5- (3-propyl- Pyrrolidine -3- Carbonyl ) - Indazole -One- Carboxylic acid tert -Butyl ester

5- (3-allyl-pyrrolidine-3-carbonyl) -indazole-1-carboxylic acid tert -butyl ester was added to steps 3 and 4 of Example 1, except that benzyl bromide was replaced with allyl iodide. Prepared as described. Pd / C (10%, Degussa catalyst type E101 NE / W, 100 mg) was added 5- (3-allyl-pyrrolidine-3-carbonyl) -indazole-1 in MeOH (10 mL). To a solution of carboxylic acid tert -butyl ester (200 mg, 0.56 mmol). The resulting mixture was stirred for 2.5 h under hydrogen atmosphere (balloon pressure). The reaction mixture is then filtered through a pad of celite and the filtrate is evaporated under reduced pressure to give 207 mg of crude 5- [hydroxy- (3-propyl-pyrrolidin-3-yl) -methyl] -indazole-1 -Carboxylic acid tert -butyl ester was obtained as off-white foam. This material was dissolved in toluene (8 mL) and activated manganese dioxide (85%, 240 mg, 2.80 mmol) was added. The resulting mixture was heated at 100 ° C. for 3 hours and then cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the resulting residue was purified by flash chromatography to give 86 mg of 5- (3-propyl-pyrrolidine-3-carbonyl) -indazole-1-carboxylic acid tert -butyl ester as a white foam. Obtained as a mold solid.

Step 2: (1 H - Indazole -5-yl)-(3-propyl- Pyrrolidine -3 days)- Methanone Hydrochloride

5- (3-propyl-pyrrolidine-3-carbonyl) -indazole-1-carboxylic acid tert -butyl ester was deprotected following the procedure described in step 4 of Example 2 to give (1 H -indazole- 5-yl)-(3-propyl-pyrrolidin-3-yl) -methanone hydrochloride was obtained as a white powder. MS = 258 [M + H] ⁺ .

Using the procedure described above and appropriate starting materials, the following compounds were prepared:

( 1H -Indol-5-yl)-(3-propyl-pyrrolidin-3-yl) -methanone hydrochloride, MS = 257 [M + H] < + >;

(3-butyl-pyrrolidin-3-yl)-(1 H -indol-5-yl) -methanone hydrochloride, MS = 271 [M + H] < + >; And

( 1H -Indol-5-yl)-[3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone hydrochloride, MS = 285 [M + H] < + >.

Additional compounds prepared by the above procedure are shown in Table 1.

Example 4

(1H-Indol-5-yl)-(3-phenyl-pyrrolidin-3-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme J below.

Scheme J

Step 1: 6-phenyl-7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid methyl ester

Triethylamine (2.6 mL, 19.15 mmol) was added to a suspension of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.50 g, 7.66 mmol) in DCM (30 mL). The resulting mixture was stirred for 5 minutes until the solids completely dissolved, then cooled to 0 ° C. and methyl chloroformate (0.65 mL, 8.43 mmol) was added dropwise. A thick white precipitate formed. The reaction mixture was allowed to warm to rt, stirred for 1 h, then quenched by addition of water and extracted with DCM. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to yield 1.75 g of 4-phenyl-3,6-dihydro-2 H -pyridine-1-carboxylic acid methyl ester as pale yellow oil. This crude product (7.66 mmol) was dissolved in chloroform (30 mL) and 3-chloroperoxybenzoic acid (77%, 2.22 g, 9.95 mmol) was added. The resulting solution was stirred at rt for 18 h. An aqueous Na ₂ SO ₃ (20%, 30 mL) solution was added and the resulting mixture was vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and evaporated under reduced pressure to give a pale yellow oil. This crude oil was purified by flash chromatography (10% -20% EtOAc in hexanes) to 1.68 g (94% two-step yield) of 6-phenyl-7-oxa-3-aza-bicyclo [4.1.0] Heptane-3-carboxylic acid methyl ester was obtained as a colorless oil.

Step 2: 3-formyl-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester

Boron trifluoride diethyl etherate (1.82 mL, 14.40 mmol) was added 6-phenyl-7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid methyl ester (1.68 g, 7.20 mmol) at room temperature. Was added slowly to the solution. A slightly exothermic reaction was observed and after 5 minutes the reaction mixture was quenched by the slow addition of saturated aqueous NaHCO ₃ (50 mL). The resulting mixture is extracted with EtOAc and the combined organic extracts are washed with water, dried over MgSO ₄ , filtered and evaporated under reduced pressure to yield 1.63 g (97% yield) of 3-formyl-3-phenyl-pyrrolidine-. 1-carboxylic acid methyl ester was obtained as a pale yellow oil, which was used without further purification.

Step 3: 3- [ Hydroxy -(One- Triisopropylsilane -One H -Indole-5-day)- methyl ] -3-phenyl- Pyrrolidine -One- Carboxylic acid methyl  Ester

Tert -butyllithium (1.7 M in pentane, 8.9 mL, 15.10 mmol) was added 5-bromo-1-triisopropylsilaneyl-1 H -indole (2.42 g) in THF (25 mL) under nitrogen atmosphere at -78 ° C. , 6.86 mmol) in solution. The resulting pale yellow solution was stirred at −78 ° C. for 15 minutes, then a solution of 3-formyl-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester (1.60 g, 6.86 mmol) in THF (5 mL) was added. Added slowly. The reaction mixture was stirred at −78 ° C. for 30 minutes and then warmed to room temperature over 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl and diluted with water. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% -50% EtOAc in hexanes) to 1.76 g (51% yield) of 3- [hydroxy- (1-triisopropylsilylyl-1 H -indole-5- Yl) -methyl] -3-phenyl-pyrrolidine-1-carboxylic acid methyl ester as a white foamy solid.

Step 4: 3- (1 H -Indole-5-carbonyl) -3-phenyl-pyrrolidine-1-carboxylic acid methyl ester

Manganese dioxide (85%, 256 mg, 2.95 mmol) was added to 3- [hydroxy- (1-triisopropylsilaneyl-1 H -indol-5-yl) -methyl] -3-phenyl in toluene (8 mL). Add to a solution of pyrrolidine-1-carboxylic acid methyl ester (300 mg, 0.59 mmol). The reaction mixture was heated at 100 ° C. for 2 hours, then cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated under reduced pressure to give 326 mg of 3-phenyl-3- (1-triisopropylsilylyl-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid methyl ester as a colorless foamy oil. Obtained. A portion of this product (298 mg, 0.59 mmol) was dissolved in THF (8 mL) and a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.60 mL, 0.59 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 20 minutes and then quenched by addition of water. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% -50% EtOAc in hexanes) to 167 mg (81% two-step yield) of 3- (1 H -indole-5-carbonyl) -3-phenyl-pyrroli Dean-1 -carboxylic acid methyl ester was obtained as white foam.

4- ( 1H -Indol-5-carbonyl) -4-phenyl-piperidine-1-carboxylic acid tert -butyl ester, 4-formyl-4-phenyl-piperidine-1-carboxylic acid tert -butyl Prepared according to the procedure described above using an ester (prepared as described in preparation 5).

Step 5: (1 H -Indol-5-yl)-(3- Phenyl - Pyrrolidine -3 days)- Methanone

Sodium ethanethiolate (113 mg, 1.35 mmol) was added 3- (1 H -indole-5-carbonyl) -3-phenyl-pyrrolidine-1-carboxylic acid methyl ester (157 mg, 0.45) in DMF (3 mL). mmol) solution. The resulting mixture was heated at 100 ° C. for 2 hours and then at 120 ° C. for an additional 2 hours. The reaction mixture was cooled to room temperature and quenched by addition of water. The resulting mixture is extracted with EtOAc and the combined organic extracts are washed with water, dried over MgSO ₄ , filtered and evaporated under reduced pressure to give 230 mg of oil which is flash chromatography (MeOH / DCM / NH ₄ OH). Purification with hexane gave 15 mg of (1 H -indol-5-yl)-(3-phenyl-pyrrolidin-3-yl) -methanone. MS = 291 [M + H] ⁺ .

Similarly (1 H -indol-5-yl)-(4-phenyl-piperidin-4-yl) -methanone was prepared. MS = 305 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 5

(3-benzyl-pyrrolidin-3-yl)-(1-methyl-1H-indol-5-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme K below.

Scheme K

Step 1: 3-benzyl-3- (1- methyl -One H -Indole-5- Carbonyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester

Sodium hydride (60% in inorganic oil, 12 mg, 0.296 mmol) was dissolved in 3-benzyl-3- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid in DMF (3 mL) at room temperature. to a solution of tert -butyl ester (100 mg, 0.247 mmol). The resulting mixture was stirred at rt for 20 min before methyliodide (18 μL, 0.296 mmol) was added. The reaction mixture was then stirred for 30 minutes, then quenched by addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure to 105 mg of 3-benzyl-3- (1-methyl-1 H -indole-5-carbonyl) -pi Lolidine-1-carboxylic acid tert -butyl ester was obtained as a white foam, which was used without further purification.

Step 2: (3-benzyl- Pyrrolidine -3-yl)-(1- methyl -One H -Indole-5-day)- Methanone

3-benzyl-3- (1-methyl-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was deprotected as described in step 4 of Example 1 (3- Benzyl-pyrrolidin-3-yl)-(1-methyl-1 H -indol-5-yl) -methanone was obtained as hydrochloride salt. MS = 319 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 6

(3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme L below.

Scheme L

Step 1: 3- (3,4-Dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

tert -butyllithium (1.7 M in pentane, 2.5 mL, 4.25 mmol) of 4-bromo-1,2-dichlorobenzene (435 mg, 1.93 mmol) in THF (10 mL) at -78 ° C. under nitrogen atmosphere. To the solution. The resulting solution was stirred at −78 ° C. for 15 minutes, then 3- (methoxy-methyl-carbamoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (500 mg, 1.93 mmol) in THF (2 mL) ) Was slowly added. The reaction mixture was stirred at −78 ° C. for 20 minutes and then warmed to room temperature over 30 minutes. The reaction was quenched by addition of saturated aqueous NH ₄ Cl, then diluted with water and extracted with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give an oil which was purified by flash chromatography (10% -30% EtOAc in hexanes) to 143 mg (22% yield) of 3- (3,4-Dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a colorless oil.

Step 2: 3-benzyl-3- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Benzyl bromide (0.19 mL, 1.60 mmol) was added to a solution of 3- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (138 mg, 0.40 mmol) in THF (5 mL). After addition, lithium bis (trimethylsilyl) amide (1.0 M in THF, 1.2 mL, 1.20 mmol) was added slowly at room temperature. The reaction mixture was stirred at rt for 1.5 h, then quenched by addition of saturated aqueous NH ₄ Cl, diluted with water and extracted with EtOAc. The combined organic extracts were ±± coated on MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% -20% EtOAc in hexanes) to 40 mg (23% yield) of 3-benzyl-3- (3,4-dichloro-benzoyl) -pyrrolidine-1 -Carboxylic acid tert -butyl ester was obtained as a colorless oil.

Step 3: 3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl) -methanone

Trifluoroacetic acid (0.3) in a solution of 3-benzyl-3- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (40 mg, 0.092 mmol) in DCM (3 mL) mL) was added at room temperature. The reaction mixture was stirred at rt for 1 h, then poured into aqueous NaOH (1.0 M), diluted with water and extracted with DCM. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (3%-10% MeOH + 0.5% NH ₄ OH in DCM) to 15 mg (48% yield) of 3-benzyl-pyrrolidin-3-yl)-(3 , 4-Dichloro-phenyl) -methanone was obtained as a yellow oil. This material is dissolved in DCM, HCl solution (1.0 M in Et ₂ O, 1.1 equiv) is added, the resulting mixture is concentrated under reduced pressure and the residue is triturated with Et ₂ O to give 17 mg of 3-benzyl-P. Ralidin-3-yl)-(3,4-dichloro-phenyl) -methanone hydrochloride was obtained as a white solid. MS = 334 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 7

5- (3-benzyl-pyrrolidine-3-carbonyl) -1,3-dihydro-indol-2-one hydrochloride

The synthesis procedure described in this example was carried out according to the process shown in Scheme M below.

Scheme M

Step 1: 3-benzyl-3- (3,3-dibromo-2-oxo-2,3-dihydro-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester and 3-benzyl-3- (3-bromo-2-oxo-2,3-dihydro-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Freshly recrystallized N-bromosuccinimide (278 mg, 1.56 mmol) was added 3-benzyl-3- (1 H -indole-5-carbonyl) in a mixture of t-BuOH / water (5% water, 8.40 mL). To the solution of -pyrrolidine-1-carboxylic acid tert -butyl ester (210 mg, 0.52 mmol) was added several fractions at room temperature over 5 minutes. The reaction mixture was stirred for 1.5 h at room temperature and then concentrated under reduced pressure. The residue was partitioned between water and DCM and the combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30%-60% EtOAc in hexanes) to 129 mg (43% yield) of 3-benzyl-3- (3,3-dibromo-2-oxo-2,3- Dihydro- 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a pale yellow foamy solid, 67 mg (26% yield) of 3-benzyl-3- (3 Bromo-2-oxo-2,3-dihydro- 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as a pale yellow foamy solid.

Step 2: 3-benzyl-3- (2-oxo-2,3-dihydro-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

Zinc powder (130 mg, 2.00 mmol) was added to 3-benzyl-3- (3,3-dibromo-2-oxo-2,3-dihydro-1 H -indole-5-carbonyl in acetic acid (4 mL). To a solution of) -pyrrolidine-1-carboxylic acid tert -butyl ester (115 mg, 0.20 mmol). The reaction mixture was stirred vigorously for 1 hour at room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to afford 3-benzyl-3- (2-oxo-2,3-dihydro-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was obtained as foam. The same procedure was used with 3-benzyl-3- (3-bromo-2-oxo-2,3-dihydro- 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester And repeated.

Step 3: 5- (3-benzyl-pyrrolidine-3-carbonyl) -1,3-dihydro-indol-2-one hydrochloride

3-benzyl-3- (2-oxo-2,3-dihydro-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester was removed according to the procedure described in Example 3. Protection gave 5- (3-benzyl-pyrrolidine-3-carbonyl) -1,3-dihydro-indol-2-one hydrochloride as off-white powder. MS = 321 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 8

(2-benzyl-pyrrolidin-2-yl)-(1H-indol-5-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme N below.

Scheme N

Step 1: 2-benzyl-2- (1-triisopropylsilylyl-1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

To a stirred solution of 5-bromo-1-triisopropylsilylyl-1 H -indole (0.55 g, 1.57 mmol) in THF (10 mL) under nitrogen atmosphere at −78 ° C. 1.55 M solution in pentane, 3.13 mmol) was added dropwise. After 1 h, the reaction mixture was cold of (R) -2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.50 g, 3.13 mmol) in THF (10 mL). It was added quickly to the (-78 ° C) solution. The reaction mixture was stirred at -78 ° C for 1 hour, then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched by addition of saturated aqueous NH ₄ Cl (20 mL) and then extracted with EtOAc. The combined extracts were washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-20% EtOAc in hexane) 2-benzyl-2- (1-triisopropylsilaneyl-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert Butyl ester (0.145 g, 0.259 mmol, 16%) was obtained as a colorless gum.

The following compounds were also prepared using the appropriate starting materials:

2-Butyl-2- (1-triisopropylsilanyl-1 H -indazole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (yellow oil, 31%).

Step 2: 2-benzyl-2- (1 H -Indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

2-benzyl-2- (1-triisopropylsilanyl-1 H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.145) in THF (5 mL) under nitrogen at ambient temperature g, 0.259 mmol) was added TMAF (0.026 g, 0.285 mmol). After 1 hour, the reaction mixture was concentrated in vacuo. Purify the residue by chromatography (silica, 25-50% EtOAc in hexanes) to give 2-benzyl-2- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.045 g, 0.111 mmol, 43%) was obtained as a colorless foam.

The following compounds were also prepared using the appropriate starting materials:

2-Butyl-2- ( 1H -indazol-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (yellow solid, 25%).

Step 3: (2-benzyl-pyrrolidin-2-yl)-(1 H -Indol-5-yl) -methanone

2-benzyl-2- ( 1H -indole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.045 g, 0.111 mmol) in 1N HCl in MeOH (2.2 mL) at nitrogen at ambient temperature The solution of was stirred for 14 hours. Aqueous NaOH (4 N, 0.6 mL) was added and the reaction mixture was extracted with DCM. The combined extracts were washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. Purify the residue by chromatography (silica, 0-10% 9: 1 MeOH: NH ₄ OH solution in DCM) to give (2-benzyl-pyrrolidin-2-yl)-(1 H -indole-5- Il) -methanone (0.021 g, 0.069 mmol, 62%) was obtained as a colorless solid. MS = 305 [M + H] ⁺ .

The following compounds were also prepared using the appropriate starting materials:

(2-butyl-pyrrolidin-2-yl)-( 1H -indazol-5-yl) -methanone (yellow solid, 100%), MS = 306 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  9

(2-butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme O below.

Scheme O

Step 1: 2-Butyl-2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -pyrrolidine-1-carboxylic acid tert -Butyl ester

3,4-dichloro in a stirred solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.753 g, 2.95 mmol) in THF (12 mL) at 0 ° C. and under nitrogen. Phenylmagnesium bromide (0.5M solution in 11.8 mL of pentane, 5.9 mmol) was added dropwise over 10 minutes. After 20 minutes, the reaction mixture was quenched by addition of saturated aqueous NH ₄ Cl (30 mL) and then extracted with EtOAc. The combined extracts were washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil (1.9 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) to 2-butyl-2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -pyrrolidine-1-carboxylic acid tert -butyl Ester (0.548 g, 1.36 mmol, 46%) was obtained as a colorless gum and as an inseparable mixture of diastereomers.

The following compounds were also prepared using the appropriate starting materials:

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (pale yellow oil, 47%);

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -2-ethoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 59%);

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -2- (3,3-difluoro-allyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 42 %);

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -5,5-dimethyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless foam, 81%);

(2R, 4R) -4- ( tert -Butyl-dimethyl-silanyloxy) -2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -2-propyl-pyrrolidine-1 Carboxylic acid tert -butyl ester (colorless gum, 70%);

(2S, 4R) -4- ( tert -Butyl-dimethyl-silanyloxy) -2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -2-propyl-pyrrolidine-1 Carboxylic acid tert -butyl ester (colorless oil, 45%);

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -2-propyl-azetidine-1-carboxylic acid tert -butyl ester (colorless oil, 21%) as a single diastereomer;

2-[(3,4-Dichloro-phenyl) -hydroxy-methyl] -2-propyl-piperidine-1-carboxylic acid tert -butyl ester (colorless oil, 10%).

Step 2: 2-butyl-2- (3,4- Dichloro - Benzoyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester

2-butyl-2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -pyrrolidine-1-carboxylic acid tert -butyl ester (0.520 g, in DCM (20 mL) at 0 ° C. under nitrogen. 1.29 mmol) was added DMP (0.658 g, 1.55 mmol) in a single fraction. The reaction mixture is allowed to warm to ambient temperature, stirred for 30 minutes, diluted with DCM, washed with 1N NaOH and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to a yellow oil (0.62 g) Obtained. Purification by chromatography (silica, 10-20% EtOAc in hexanes) to 2-butyl-2- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.441 g, 1.10 mmol) , 85%) was obtained as a clear colorless gum.

The following compounds were also prepared using the appropriate starting materials:

2- (3,4-Dichloro-benzoyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (white solid, 88%);

2- (3,4-Dichloro-benzoyl) -2-ethoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless residue, 75%);

2- (3,4-Dichloro-benzoyl) -2- (3,3-difluoro-allyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (yellow oil, 81%);

2- (3,4-Dichloro-benzoyl) -5,5-dimethyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 83%);

(2R, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2- (3,4-dichloro-benzoyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester ( Colorless gum, 73%);

(2S, 4R) -4- ( tert -butyl-dimethyl-silanyloxy) -2- (3,4-dichloro-benzoyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester ( Colorless oil, 83%);

2- (3,4-Dichloro-benzoyl) -2-propyl-azetidine-1-carboxylic acid tert -butyl ester (colorless residue, 58%);

2- (3,4-Dichloro-benzoyl) -2-propyl-piperidine-1-carboxylic acid tert -butyl ester (colorless oil, 80%).

Step 3: (2-butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl) -methanone

A solution of 2-butyl-2- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.435 g, 1.09 mmol) in 1N HCl in MeOH (10.9 mL) at ambient temperature Stir under nitrogen for 14 hours. The reaction mixture was concentrated in vacuo, then redissolved in DCM and concentrated in vacuo to remove excess HCl. Purification by chromatography (silica, 0-10% MeOH in DCM) gave (2-butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl) -methanone (0.249 g, 0.740 mmol, 68%) was obtained as a white powder. MS = 300 [M + H] ⁺ .

The following compounds were prepared in a similar manner using the appropriate starting materials:

(3,4-Dichloro-phenyl)-(2-propyl-pyrrolidin-2-yl) -methanone (grey-white solid, 81%); MS = 286 [M + H] ⁺ ;

(3,4-Dichloro-phenyl)-(2-ethoxymethyl-pyrrolidin-2-yl) -methanone (white solid, 99%); MS = 302 [M + H] ⁺ ;

(3,4-Dichloro-phenyl)-[2- (3,3-difluoro-allyl) -pyrrolidin-2-yl] -methanone (white powder, 97%); MS = 320 [M + H] ⁺ ;

(3,4-Dichloro-phenyl)-(5,5-dimethyl-2-propyl-pyrrolidin-2-yl) -methanone (pale yellow powder, 97%); MS = 314 [M + H] ⁺ ;

(3,4-Dichloro-phenyl)-(2-propyl-azetidin-2-yl) -methanone (white powder, 30%), after analytical HPLC purification; MS = 272 [M + H] ⁺ ; And

(3,4-Dichloro-phenyl)-(2-propyl-piperidin-2-yl) -methanone (yellow solid, 97%), MS = 300 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 10

(4-Amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme P below.

Scheme P

Step 1: 2-Butyl-2-{[3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazan-2-yl) -phenyl] -hydroxy-methyl} -Pyrrolidine-1-carboxylic acid tert -Butyl ester

2- (4-bromo-2-chloro-phenyl) -1,1,1,3,3,3-hexamethyl-disilazane (0.484 g, in -78 < 0 > C and under nitrogen in ether (14 mL) 1.38 mmol) was added dropwise tert-butyllithium (2.03 mL, 1.43M solution in pentane, 2.91 mmol). After 90 minutes, a solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.353 g, 1.38 mmol) in ether (3 mL) was added dropwise to the reaction mixture. After 1 hour, the reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 30 minutes. The reaction mixture was quenched by addition of saturated aqueous NH ₄ Cl (10 mL) and extracted with EtOAc. The combined extracts were washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to oil (0.75 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) afforded 2-butyl-2-{[3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazane- 2-yl) -phenyl] -hydroxy-methyl} -pyrrolidine-1-carboxylic acid tert -butyl ester (0.357 g, 0.678 mmol, 49%) was obtained as a colorless oil.

The following compounds were also prepared using the appropriate starting materials:

2-{[3-Chloro-4- (1,1,1,3,3,3-hexamethyl-disilazan-2-yl) -phenyl] -hydroxy-methyl} -2-propyl-pyrroli Dean-1-carboxylic acid tert -butyl ester (colorless foam, 43%);

2- [hydroxy- (1-triisopropylsilanyl-1 H -indazol-5-yl) -methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow foam, 50% );

2-{[1- ( tert -Butyl-dimethyl- silanyl ) -7-fluoro-1 H -indol-5-yl] -hydroxy-methyl} -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (white solid, 49%); And

2-cyclopropylmethyl-2- [hydroxy- (1-triisopropylsilanyl- 1H -indazol-5-yl) -methyl] -pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 62%).

Step 2: 2-butyl-2- [3- Chloro -4- (1,1,1,3,3,3- Hexamethyl - Disilazane -2 days)- Benzoyl ]- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

2-butyl-2-{[3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-in DCM (10 mL) at nitrogen at ambient temperature To a stirred solution of phenyl] -hydroxy-methyl} -pyrrolidine-1-carboxylic acid tert -butyl ester (0.357 g, 0.678 mmol) was added DMP (0.575 g, 1.36 mmol) in a single fraction. After 1 hour the reaction mixture was diluted with DCM, washed with 1N NaOH and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to a brown residue (0.290 g). Purification by chromatography (silica, 10% EtOAc in hexanes) to 2-butyl-2- [3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazan-2-yl ) -Benzoyl] -pyrrolidine-1-carboxylic acid tert -butyl ester (0.208 g, 0.397 mmol, 58%) was obtained as a clear colorless residue.

The following compounds were also prepared using the appropriate starting materials:

2- [3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazane di-2-yl) benzoyl] pyrrolidine-1-carboxylic acid tert - Butyl ester (yellow oil, 96%);

2-propyl-2- (1-triisopropylsilanyl-1 H -indazol-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (yellow foam, 77%);

2- [1- ( tert -Butyl-dimethyl- silanyl ) -7-fluoro- 1H -indole-5-carbonyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow Oil, 75%);

2-cyclopropylmethyl-2- (1-triisopropylsilaneyl-1 H -indazol-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 27%).

Step 3: (4-Amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl) -methanone

2-butyl-2- [3-chloro-4- (1,1,1,3,3,3-hexamethyl-disilazan-2-yl) -benzoyl]-in methanolic 1N HCl (7.8 mL)- A solution of pyrrolidine-1-carboxylic acid tert -butyl ester (0.205 g, 0.391 mmol) was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated in vacuo to afford (4-amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl) -methanone (0.249 g, quantitative yield) as a light brown powder and monohydrochloride Obtained as a salt.

The following compounds were also prepared by the above procedure using the appropriate starting materials:

(4-amino-3-chloro-phenyl)-(2-propyl-pyrrolidin-2-yl) -methanone (beige solid, 83%), MS = 267 [M + H] ⁺ ;

( 1H -indazol-5-yl)-(2-propyl-pyrrolidin-2-yl) -methanone (yellow solid, 57%), MS = 258 [M + H] ⁺ ;

(7-fluoro-1 H -indol-5-yl)-(2-propyl-pyrrolidin-2-yl) -methanone (light brown foam, 60%), MS = 275 [M + H] ⁺ ;

(2-cyclopropylmethyl-pyrrolidin-2-yl)-(1 H -indazol-5-yl) -methanone (white powder, 99%), MS = 270 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  11

(2-propyl- Pyrrolidine 2-yl)-(1 H - Pyrrolo [2,3- b ] Pyridine -5 days)- Methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme Q below.

Scheme Q

Step 1: 2- [hydroxy- (1-triisopropylsilylyl-1 H -Pyrrolo [2,3- b ] Pyridin-5-yl) -methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -Butyl ester

Stirred solution of 5-bromo-1-triisopropylsilanyl-1 H -pyrrolo [2,3- b ] pyridine (0.587 g, 1.66 mmol) in ether (20 mL) at -78 ° C and under nitrogen To tert-butyllithium (1.51 M solution in 2.30 mL of pentane, 3.49 mmol) was added dropwise. After 90 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.400 g, 1.66 mmol) in ether (1 mL) was added dropwise to the reaction mixture. After stirring for one hour, the reaction mixture was allowed to warm to ambient temperature over 30 minutes. The reaction mixture was quenched by addition of saturated aqueous NH ₄ Cl (20 mL) and then extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO ₃ and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil (0.90 g). Purification by chromatography (silica, 5-20% EtOAc in hexane) 2- [hydroxy- (1-triisopropylsilylyl-1 H -pyrrolo [2,3- b ] pyridin-5-yl)- Methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.576 g, 1.12 mmol, 53%) was obtained as a colorless gum.

The following compounds were also prepared using the appropriate starting materials:

2- [hydroxy- (1-triisopropylsilanyl-1 H -indazol-5-yl) -methyl] -2-isopropoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow oil , 79%); And

2- [hydroxy- (1-triisopropylsilanyl-1 H -indazol-5-yl) -methyl] -2-isobutyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 56 %).

Step 2: 2-propyl-2- (1- Triisopropylsilane -One H - Pyrrolo [2,3- b ] Pyridine -5-car Bo Neil) Pyrrolidine -One- Carboxylic acid tert -Butyl ester

2- [hydroxy- (1-triisopropylsilanyl-1 H -pyrrolo [2,3- b ] pyridin-5-yl) -methyl] -2- in DCM (15 mL) at nitrogen at ambient temperature. To a stirred solution of propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.528 g, 1.03 mmol) was added DMP (0.652 g, 1.54 mmol) in a single fraction. After 90 minutes the reaction mixture was diluted with DCM, washed with 1N NaOH and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to a brown oil. Purification by chromatography (silica, 5-10% EtOAc in hexanes) to 2-propyl-2- (1-triisopropylsilylyl-1 H -pyrrolo [2,3- b ] pyridine-5-carbonyl) -Pyrrolidine -1-carboxylic acid tert -butyl ester (0.415 g, 0.809 mmol, 79%) was obtained as a yellow gum.

The following compounds were also prepared using the appropriate starting materials:

2-isopropoxymethyl-2- (1-triisopropylsilylyl-1 H -indazole-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (yellow solid, 96%); And

2-isobutyl-2- (1-triisopropylsilaneyl-1 H -indazol-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 49%).

Step 3: 2-propyl-2- (1 H -Pyrrolo [2,3- b ] Pyridine-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -Butyl ester

2-propyl-2- (1-triisopropylsilanyl-1 H -pyrrolo [2,3- b ] pyridine-5-carbonyl) -pyrrolidine- in THF (7.5 mL) at nitrogen at ambient temperature. To a stirred solution of 1-carboxylic acid tert -butyl ester (0.415 g, 0.809 mmol) was added TMAF (0.753 g, 8.09 mmol). The reaction mixture was stirred for 1 h, then diluted with saturated aqueous NaHCO ₃ (30 mL) and water (15 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to a pale yellow gum. Purification by chromatography (silica, 50-100% EtOAc in hexanes) to 2-propyl-2- ( 1H -pyrrolo [2,3- b ] pyridine-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.247 g, 0.692 mmol, 86%) was obtained as a colorless foam.

The following compounds were also prepared using the appropriate starting materials:

2- ( 1H -indazol-5-carbonyl) -2-isopropoxymethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (white foam, 68%);

2- ( 1H -indazol-5-carbonyl) -2-isobutyl-pyrrolidine-1-carboxylic acid tert -butyl ester (yellow foam, 30%);

(2R, 4R) -2- (3, 4-Dichloro-benzoyl) -4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless residue, 79%);

(2S, 4R) -2- (3,4-Dichloro-benzoyl) -4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless gum, 79%).

Step 4: (2-propyl- Pyrrolidine 2-yl)-(1 H - Pyrrolo [2,3- b ] Pyridine -5 days)- Methanone

2-propyl-2- ( 1H -pyrrolo [2,3- b ] pyridine-5-carbonyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.240 g in 1N methanolic HCl (10.1 mL) , 0.672 mmol) was stirred at 20 ° C. under nitrogen for 18 h. The reaction mixture was concentrated in vacuo, then triturated with DCM (5 mL) and concentrated in vacuo to (2-propyl-pyrrolidin-2-yl)-(1 H -pyrrolo [2,3- b ] pyridine -5-yl) -methanone (0.215 g, 0.652 mmol, 97%) was obtained as a white powder and monohydrochloride salt. MS = 258 [M + H] ⁺ .

The following compounds were also prepared using the appropriate starting materials:

( 1H -indazol-5-yl)-(2-isopropoxymethyl-pyrrolidin-2-yl) -methanone (white solid, 94%), MS = 288 [M + H] ⁺ ;

( 1H -indazol-5-yl)-(2-isobutyl-pyrrolidin-2-yl) -methanone (yellow powder, 100%), MS = 272 [M + H] ⁺ ;

(3,4-Dichloro-phenyl)-((2R, 4R) -4-hydroxy-2-propyl-pyrrolidin-2-yl) -methanone (white solid, 61%), MS = 302 [ M + H] ⁺ ; And

(3,4-Dichloro-phenyl)-((2S, 4R) -4-hydroxy-2-propyl-pyrrolidin-2-yl) -methanone (white solid, 97%), MS = 302 [ M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  12

(5,6-Dichloro-pyridin-2-yl)-(2-propyl-pyrrolidin-2-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme R below.

Scheme R

Step 1: 2-[(5,6- Dichloro -Pyridin-2-yl)- Hydroxy - methyl ] -2-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

To a stirred solution of 2-bromo-5,6-dichloro-pyridine (0.500 g, 2.20 mmol) in THF (6 mL) under nitrogen at 0 ° C. isopropylmagnesium chloride (2M solution in 1.21 mL of THF, 2.42 mmol) was added dropwise. After 2 h, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.317 g, 1.32 mmol) in THF (1 mL) was added dropwise to the reaction mixture. After 30 minutes, the reaction mixture was allowed to warm to ambient temperature, stirred for 1 hour, then quenched by addition of saturated aqueous NH ₄ Cl (10 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. Purify the residue by chromatography (silica, 0-40% EtOAc in hexanes) to afford 2-[(5,6-dichloro-pyridin-2-yl) -hydroxy-methyl] -2-propyl-pyrrolidine -1-carboxylic acid tert -butyl ester (0.289 g, 0.745 mmol, 56%) was obtained as a yellow oil and as an inseparable mixture of diastereomers.

Using appropriate starting materials, 2-[(4,5-dichloro-pyridin-2-yl) -hydroxy-methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (orange oil, 19%) was also prepared using the above procedure.

Step 2: 2- (5,6- Dichloro Pyridine-2- Carbonyl ) -2-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

2-[(5,6-Dichloro-pyridin-2-yl) -hydroxy-methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester in DCM (12 mL) at 0 ° C. under nitrogen. To a stirred solution of (0.288 g, 0.742 mmol) DMP (0.315 g, 0.742 mmol) was added in a single fraction. The reaction mixture was stirred for 1 h, then quenched with a 1: 1 mixture of 10% aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ (50 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were concentrated in vacuo to afford 2- (5,6-dichloro-pyridine-2-carbonyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.280 g, 0.725 mmol, 98% ) Was obtained as a yellow solid, which was used directly without further purification.

Using appropriate starting materials, 2- (4,5-dichloro-pyridine-2-carbonyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (colorless oil, 43%) is also prepared. It was.

Step 3: (5,6- Dichloro -Pyridin-2-yl)-(2-propyl- Pyrrolidine -2 days)- Methanone

Of 2- (5,6-dichloro-pyridine-2-carbonyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.280 g, 0.725 mmol) in 1N HCl in MeOH (3 mL) The solution was stirred at ambient temperature under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography (silica, 0-30% MeOH in DCM) to give (5,6-dichloro-pyridin-2-yl)-(2-propyl-pi Ralidin-2-yl) -methanone (0.167 g, 0.522 mmol, 72%) was obtained as a yellow solid and monohydrochloride salt. MS = 287 [M + H] ⁺ .

Using the appropriate starting material, (4,5-dichloro-pyridin-2-yl)-(2-propyl-pyrrolidin-2-yl) -methanone (yellow gum, 37%) was also prepared. MS = 287 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  13

(3,4-Dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidin-2-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme S below.

Scheme S

Step 1: 2-[(3,4- Dichloro -5- Fluoro - Phenyl ) - Hydroxy - methyl ] -2-propyl-pyrrolidine-1- Carboxylic acid tert -Butyl ester

A stirred mixture of 3,4-dichloro-5-fluorophenyl bromide (1.38 g, 5.66 mmol) and magnesium turning (0.145 g, 5.94 mmol) in THF (8 mL) was added under reflux for 30 minutes under nitrogen. After being heated to 0 ° C. To the reaction mixture was added dropwise a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.682 g, 2.38 mmol) in THF (2 mL) over 15 minutes. The cold reaction mixture was stirred for 1 h, then quenched by addition of saturated aqueous NH ₄ Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil (1.7 g). Purification by chromatography (silica, 0-20% EtOAc in hexanes) to give 2-[(3,4-dichloro-5-fluoro-phenyl) -hydroxy-methyl] -2-propyl-pyrrolidine-1 -Carboxylic acid tert -butyl ester (0.571 g, 1.41 mmol, 50%) was obtained as a white solid.

Step 2: 2- (3,4- Dichloro -5- Fluoro - Benzoyl ) -2-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

2-[(3,4-Dichloro-5-fluoro-phenyl) -hydroxy-methyl] -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl in DCM (20 mL) at 0 ° C. under nitrogen. To a stirred solution of ester (0.533 g, 1.31 mmol) was added DMP (0.557 g, 1.55 mmol) in single fraction. The reaction mixture was allowed to warm to ambient temperature and stirred for 90 minutes. A second fraction of DMP (0.110 g, 0.26 mmol) was added and the reaction mixture was stirred for 30 minutes, then diluted with DCM, washed with 1N NaOH and brine (20 mL), dried (MgSO ₄ ), Filtration and concentration in vacuo gave a clear colorless oil (0.55 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) to give 2- (3,4-dichloro-5-fluoro-benzoyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester ( 0.358 g, 0.886 mmol, 68%) was obtained as a clear colorless gum.

Step 3: (3,4- Dichloro -5- Fluoro - Phenyl )-(2-propyl- Pyrrolidine -2 days)- Methanone

Of 2- (3,4-dichloro-5-fluoro-benzoyl) -2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.346 g, 0.856 mmol) in 1N methanolic HCl (8.6 mL) The solution was stirred at ambient temperature under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo, then redissolved in DCM and re-concentrated in vacuo to remove excess HCl (3,4-dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidine -2-yl) -methanone (0.294 g, quantitative yield) was obtained as a white powder. MS = 304 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 14

(3,4-Dichloro-phenyl)-((2R, 4S) -4-fluoro-2-propyl-pyrrolidin-2-yl) -methanone and (3,4- Dichloro - Phenyl )-((2S, 4S) -4- Fluoro -2-propyl- Pyrrolidine -2 days)- Methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme T below.

Scheme T

Step 1: (R) -4- ( tert Butyl Dimethyl - Silanyloxy ) -2-propyl-2-[(3,4- Dichloro - Phenyl ) - Hydroxy - methyl ]- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

(R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-2-[(3,4-dichloro-phenyl) -hydroxy-methyl] -pyrrolidine-1-carboxylic acid tert -butyl ester was prepared according to the procedure of step 1 of Example 11 with 3,4-dichlorophenyl magnesium bromide and (R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-formyl- Prepared by reacting 2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester.

Step 2: (R) -4- ( tert Butyl Dimethyl - Silanyloxy ) -2-propyl-2- (3,4- Dichloro - Benzoyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester

(R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-2- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-2-[(3,4-dichloro-phenyl) -hydroxy-methyl according to the procedure of step 2 of example 11 ] -Pyrrolidine -1-carboxylic acid tert -butyl ester was prepared by oxidation with DMP.

Step 3: (R) -2- (3,4- Dichloro - Benzoyl )-4- Hydroxy -2-propyl- Pyrrolidine -1-carboxylic acid tert -Butyl ester

(R) -2- (3,4-Dichloro-benzoyl) -4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester, according to the procedure of step 3 of Example 11 ( R) -4- ( tert -butyl-dimethyl-silanyloxy) -2-propyl-2- (3,4-dichloro-benzoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester with TMAF It was prepared by.

Step 4: (S) -2- (3,4- Dichloro - Benzoyl )-4- Fluoro -2-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

(R) -2- (3,4-Dichloro-benzoyl) -4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.222) in THF (3 mL) under nitrogen at ambient temperature g, 0.554 mmol) in a stirred solution of perfluorobutanesulfonyl fluoride (0.195 mL, 1.11 mmol), triethylamine trihydrofluoride (0.181 mL, 1.11 mmol) and triethylamine (0.46 mL, 3.32 mmol ) Was added. The reaction mixture was stirred for 18 h, then filtered through a pad of silica, washed with EtOAc and concentrated in vacuo to (S) -2- (3,4-dichloro-benzoyl) -4-fluoro-2- Propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.222 g, 0.551 mmol, 99%) was obtained as a yellow foam which was used directly in the next step without further purification.

Step 5: (3,4- Dichloro - Phenyl )-((2R, 4S) -4- Fluoro -2-propyl- Pyrrolidine -2 days)- Methanone  And (3,4- Dichloro - Phenyl )-((2S, 4S) -4- Fluoro -2-propyl- Pyrrolidine -2 days)- Methanone

(S) -2- (3,4-Dichloro-benzoyl) -4-fluoro-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.220 g, in 1N methanolic HCl (3 mL) 0.545 mmol) was stirred at 20 ° C. under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and then purified by chromatography (silica, 0-20% MeOH in DCM) to give (3,4-dichloro-phenyl)-((2R, 4S) -4-fluoro-2- Propyl-pyrrolidin-2-yl) -methanone (0.048 g, 0.158 mmol, 29%) was obtained as the first fraction (yellow oil), followed by (3,4-dichloro-phenyl)-((2S , 4S) -4-fluoro-2-propyl-pyrrolidin-2-yl) -methanone (0.072 g, 0.238 mmol, 44%) is obtained as a second fraction (yellow oil), each monohydrochloride Obtained as a salt. MS = 304 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  15

(One H -Indol-5-yl)-(2-propyl-pyrrolidin-2-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme U below.

Scheme U

Step 1: 5-[(1- tert - Butoxycarbonyl -2-propyl- Pyrrolidine -2 days)- Hydroxy - methyl ] -Indole-1- Carboxylic acid tert -Butyl ester

To a stirred solution of 5-bromo-indole-1-carboxylic acid tert -butyl ester (0.700 g, 2.37 mmol) in ether (20 mL) at −78 ° C. and under nitrogen was 1.43 in tert-butyllithium (3.64 mL of pentane). M solution, 5.21 mmol) was added dropwise. After 30 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert -butyl ester (0.569 g, 2.37 mmol) in ether (5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h, then quenched by addition of saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-60% EtOAc in hexanes) afforded 5-[(1- tert -butoxycarbonyl-2-propyl-pyrrolidin-2-yl) -hydroxy-methyl] -indole- 1-carboxylic acid tert -butyl ester (0.466 g, 1.02 mmol, 43%) was obtained as a yellow oil.

Step 2: 5- (1- tert - Butoxycarbonyl -2-propyl- Pyrrolidine -2- Carbonyl ) -Indole-1- Carboxylic acid tert -Butyl ester

5-[(1- tert -butoxycarbonyl-2-propyl-pyrrolidin-2-yl) -hydroxy-methyl] -indole-1-carboxylic acid tert in DCM (10 mL) at 0 ° C. under nitrogen. To a stirred solution of butyl ester (0.460 g, 1.00 mmol) was added DMP (0.652 g, 1.54 mmol) in a single fraction. The reaction mixture is allowed to warm to ambient temperature, stirred for 90 minutes, diluted with DCM, washed with a 1: 1 mixture of 10% aqueous Na ₂ S ₂ O ₅ and NaHCO ₃ and then brine and then dried (MgSO ₄ ), filtered and concentrated in vacuo to yield a yellow oil. Purification by chromatography (silica, 0-80% EtOAc in hexanes) to give 5- (1- tert -butoxycarbonyl-2-propyl-pyrrolidine-2-carbonyl) -indole-1-carboxylic acid tert -butyl Ester (0.132 g, 0.289 mmol, 29%) was obtained as a yellow oil.

Step 3: (1 H -Indol-5-yl)-(2-propyl- Pyrrolidine -2 days)- Methanone

5- (1- tert -butoxycarbonyl-2-propyl-pyrrolidine-2-carbonyl) -indole-1-carboxylic acid tert -butyl ester (0.132 g, in DCM (3 mL) under nitrogen at 20 ° C. 0.289 mmol) was added TFA (1 mL) to the stirred solution. After 14 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic phases were concentrated in vacuo and then purified by chromatography (silica, 0-30% MeOH in DCM) to (1 H -indol-5-yl)-(2-propyl-pyrrolidin-2-yl) Methanone (0.053 g, 0.207 mmol, 72%) was obtained as a beige foam. MS = 257 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  16

Exo -(3,4- Dichloro - Phenyl )-(2-propyl-8- Keep it up - Bicyclo [3.2.1] octs -2 days)- Methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme V below.

Scheme V

Step 1: 3-oxo-8- Azabicyclo [3.2.1] octane -8- Carboxylic acid tert -Butyl ester

8-Azabicyclo [3.2.1] octan-3-one hydrochloride (Nortropinone hydrochloride, 10.0 g, 62 mmol) was dissolved in 1,4-dioxane (200 mL) and water (50 mL). N, N -diisopropylethylamine (20.0 g, 155 mmol) and di-tert-butyldicarbonate (20.3 g, 93 mmol) were added and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to afford 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester as an off-white solid (14 g, 99% Yield).

Step 2: 3- Hydroxy -8- Azabicyclo [3.2.1] Oct 2-en-2,8- Daika loft Mountain 8- tert -Butyl ester 2- methyl  Ester

The 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (14.1 g, 62 mmol) of step 1 was dissolved in cyclohexane (550 mL), and dimethyl carbonate ( 12.4 g, 137 mmol) was added followed by sodium hydride (5.0 g, 125 mmol) and methanol (0.2 mL). The reaction mixture was stirred at reflux for 15 h, then cooled to rt and water (25 mL) was added. The reaction mixture was concentrated to 50 mL volume under reduced pressure, which was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give 3-hydroxy-8-azabicyclo [3.2.1] oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl Ester 2-methyl ester was obtained as pale yellow oil (15.4 g, 87% yield).

Step 3: Endo-3- Hydroxy -8- Azabicyclo [3.2.1] octane -2,8- Dicarboxylic acid  8- tert -Butyl ester Exo -2- methyl  Ester

3-hydroxy-8-azabicyclo [3.2.1] oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (15.4 g, 54 mmol) of step 2 was dissolved in methanol ( 350 mL). The resulting solution was cooled in an acetonitrile / dry ice bath (-45 ° C.). Sodium borohydride (5.15 g, 136 mmol, 10-40 mesh) was added and the reaction mixture was stirred at -45 [deg.] C. for 1.5 h, then saturated aqueous ammonium chloride (50 mL) was added. The mixture was warmed to room temperature and then concentrated to 50 mL volume under reduced pressure, which was then partitioned between dichloromethane and saturated aqueous ammonium chloride. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give endo-3-hydroxy-8-azabicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester exo -2-methyl ester was obtained as a colorless oil (8.1 g, 52% yield).

Step 4: 8- Azabicyclo [3.2.1] Oct 2-en-2,8- Dicarboxylic acid  8- tert -Butyl ester 2- methyl  Ester

Endo-3-hydroxy-8-azabicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester exo-2-methyl ester (8.1 g, 28 mmol) of step 3 It was dissolved in 2-dichloroethane (120 mL) and triethylamine (17.2 g, 170 mmol) and trifluoroacetic anhydride (17.8 g, 85 mmol) were added. The reaction mixture was stirred at rt for 15 h, then aqueous saturated sodium bicarbonate (150 mL) and dichloromethane (280 mL) were added. The organic phase was separated and washed with brine. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give 8-azabicyclo [3.2.1] oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester Was obtained as a yellow oil (6.0 g, 79% yield).

Step 5: 8- Azabicyclo [3.2.1] octane -2,8- Dicarboxylic acid  8- tert -Butyl ester 2- methyl  Ester

Dissolve the 8-azabicyclo [3.2.1] oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (5.9 g, 22 mmol) of step 4 in ethanol (100 mL). To this was added palladium (10% on charcoal, 0.59 g). The resulting mixture was shaken for 2 hours at room temperature under hydrogen (50 psi) atmosphere, then filtered through a celite bed, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give 8-azabicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as endo (endo) and exo (exo) colorless oil (5.8 g, 97% yield) as a mixture of isomers.

Step 6: 2-propyl-8- Keep it up - Bicyclo [3.2.1] octane -2,8- Dicarboxylic acid  8-tert-butyl ester

8-azabicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1.0 g, 3.7 mmol) as a mixture of endo and exo isomers was converted to tetrahydrofuran ( 30 mL) and 1-iodopropane (3.2 g, 19 mmol) was added. The resulting solution was cooled to −76 ° C. and treated dropwise over 15 minutes with a solution of potassium bis (trimethylsilyl) amide (0.5 M, 11.1 mL, 5.6 mmol) in toluene. Stirring was continued at −76 ° C. for 1.5 hours, after which the reaction mixture was slowly warmed to 0 ° C. over 3 hours. Saturated aqueous ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give 2-propyl-8-aza-bicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl The ester was obtained as a pale yellow oil (0.99 g, 85% yield) as a mixture of endo and exo isomers.

Step 7: 2- Hydroxymethyl -2-propyl-8- Azabicyclo [3.2.1] octane -8- Kabok practice tert -Butyl ester

2-propyl-8-aza-bicyclo [3.2.1] octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (mixture of endo and exo isomers of step 6, 0.98 g, 3.1 mmol) Was dissolved in tetrahydrofuran (15 mL) and the resulting mixture was cooled to 0 ° C. Lithium aluminum hydride solution (1 M, 3.3 mL, 3.3 mmol) in tetrahydrofuran was added dropwise over 10 minutes and stirring continued at 0 ° C. for 1.5 hours. Saturated aqueous potassium sodium tartrate solution (10 mL) was added and the mixture was allowed to warm to room temperature and stirred for 15 h. A further saturated aqueous solution of potassium sodium tartrate (10 mL) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel, ethyl acetate / hexane) to separate 2-hydroxymethyl-2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester Obtained as a mixture of endo and exo isomers (0.68 g and 0.17 g, 76% and 19% yield, respectively), all of which are colorless oils.

Step 8: Exo -2- Formyl -2-propyl-8- Azabicyclo [3.2.1] octane -8- Carboxylic acid  tert-butyl ester

The exo-2-hydroxymethyl-2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (0.67 g, 2.4 mmol) of step 7 was diluted with dichloromethane (25 mL). Dissolved. The solution was cooled to 0 ° C. and Dess-Martin periodinane (1.0 g, 2.4 mmol) was added. Stirring was continued at 0 ° C. for 5 minutes and then at room temperature for 1.5 hours. To the reaction mixture was added diethyl ether (50 mL) and aqueous sodium hydroxide (1M, 20 mL) followed by additional diethyl ether (30 mL). The phases were separated and the organic phase was washed with water and brine. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the exo-2-formyl-2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester as colorless. Obtained as an oil (0.61 g, 90% yield).

Step 9: Exo -2-[(3,4- Dichlorophenyl ) - Hydroxymethyl ] -2-propyl-8- Azabicyclo [3.2.1] octane -8- Carboxylic acid tert -Butyl ester

Dissolve exo-2-formyl-2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (0.45 g, 1.6 mmol) in step 8 in tetrahydrofuran (4 mL). I was. The resulting solution was cooled to 0 ° C. and a 3,4-dichlorophenylmagnesium bromide solution in tetrahydrofuran (0.5 M, 6.4 mL, 3.2 mmol) was added dropwise over 10 minutes. Stirring was continued for 1.5 h at 0 ° C., then aqueous saturated ammonium chloride (20 mL) was added. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give exo-2-[(3,4-dichlorophenyl) -hydroxymethyl] -2-propyl-8-azabicyclo [3.2. 1] octane-8-carboxylic acid tert-butyl ester was obtained as an epimer mixture as a white solid (0.57 g, 83% yield).

Step 10: Exo -2- (3,4- Dichlorobenzoyl ) -2-propyl-8- Azabicyclo [3.2.1] octane -8- Carboxylic acid tert -Butyl ester

Exo-2-[(3,4-Dichlorophenyl) -hydroxymethyl] -2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester as epimer mixture (0.56 g, 1.3 mmol) was suspended in acetonitrile (14 mL). Dichloromethane (4 mL) was added and Dess-Martin periodinan (0.56 g, 1.3 mmol) was added to the resulting homogeneous solution and then stirred at room temperature for 1 hour. To the reaction mixture was added diethyl ether (80 mL) and aqueous sodium hydroxide (1M, 20 mL). The phases were separated and the combined organic extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / hexane) to give exo-2- (3,4-dichlorobenzoyl) -2-propyl-8-azabicyclo [3.2.1] octane-8- Carboxylic acid tert-butyl ester was obtained as off-white solid (0.53 g, 95% yield).

Step 11: Exo -(3,4- Dichloro - Phenyl )-(2-propyl-8- Azabicyclo [3.2.1] Oct -2 days) Methanone

The exo-2- (3,4-dichlorobenzoyl) -2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (0.15 g, 0.35 mmol) of step 10 was dissolved in methanol ( 1 M, 3.5 mL) in a hydrogen chloride solution and the resulting solution was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give exo- (3,4-dichloro-phenyl)-(2-propyl-8-azabicyclo [3.2.1] oct-2-yl) methanone hydrochloride as white foam (0.13 g, 99% yield).

Similarly, the endo- (3,4 according to steps 8 to 11 from the endo-2-hydroxymethyl-2-propyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester of step 7 -Dichloro-phenyl)-(2-propyl-8-azabicyclo [3.2.1] oct-2-yl) methanone hydrochloride was prepared. MS = 326 [M + H] ⁺

Additional compounds prepared by the above procedure are shown in Table 1.

Example  17

(5- Fluoro -1H-indol-2-yl)-(4-propyl-piperidin-4-yl)- Methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme W below.

Scheme W

Step 1: 1- Benzenesulfonyl -5- Fluoro -1H-indole

To a solution of 5-fluoroindole (10 g, 74 mmol) and tetrabutyl ammonium hydrogen sulphate (3.8 g, 11 mmol) in 200 mL of toluene at 0 ° C. was added 200 mL 50% aqueous NaOH, followed by benzene sulfonylchloride ( 14 mL, 111 mmol) was added. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was extracted with ethyl acetate and washed with 1M HCl, aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The remaining residue was recrystallized from ethyl acetate and hexanes to give 19 g (96% yield) of 1-benzenesulfonyl-5-fluoro-1H-indole as a white crystalline solid.

Step 2: 4-[(1- Benzenesulfonyl -5- Fluoro -1H-indol-2-yl)- Hydroxy - methyl ] -4-propyl-piperidine-1- Carboxylic acid tert -Butyl ester

T-BuLi (1.5 mL, 2.54 mmol) was slowly added to a solution of 1-benzenesulfonyl-5-fluoro-1H-indole (539 mg, 1.96 mmol) in 30 mL THF at -78 ° C. The reaction mixture was stirred for 30 minutes, then a solution of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.96 mmol) in 5 mL THF was added. The reaction was stirred for 2 h at -78 ° C, then warmed to -20 ° C and quenched with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated on silica. The material was chromatographed on 25 g Thomson column eluting with 20% ethyl acetate 80% hexanes to 4-[(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl) -hydroxy -Methyl] -4-propyl-piperidine-1-carboxylic acid tert-butyl ester (319 mg, 0.6 mmol) was obtained as a beige foam in 53% yield.

Step 3: 4- (1- Benzenesulfonyl -5- Fluoro -1H-indole-2- Carbonyl )-4-propyl-piperidine-1- Carboxylic acid tert -Butyl ester

4-[(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl) -hydroxy-methyl] -4-propyl-piperidine-1-carboxylic acid tert- in 20 mL of dichloromethane To a solution of butyl ester (319 mg, 0.6 mmol) was added Dess-Martin periodinan (255 mg, 0.6 mmol). The reaction was stirred for 30 minutes at room temperature and then quenched with a 1: 1 mixture of 5% aqueous Na ₂ S ₂ O ₃ : saturated aqueous NaHCO ₃ . The mixture was stirred until all solids dissolved and then extracted with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford crude 4- (1-benzenesulfonyl-5-fluoro-1H-indole-2-carbo Nil) -4-propyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.57 mmol) was obtained as a beige solid in 95% yield.

Step 4: 4- (5- Fluoro -1H-indole-2- Carbonyl )-4-propyl-piperidine-1- Carboxylic acid  tert-butyl ester

4- (1-benzenesulfonyl-5-fluoro-1H-indole-2-carbonyl) -4-propyl-piperidine-1-carboxylic acid tert-butyl ester in 290 mL methanol (290 mg, 0.55 mmol 10 mL of 1M NaOH was added to the solution. The reaction mixture was warmed to 80 ° C., stirred for 1 h and then concentrated in vacuo to remove methanol. The remaining residue was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford a yellow oil. The oil was chromatographed on a 12 g SiO ₂ column eluting with 20% ethyl acetate and 80% hexanes to 4- (5-fluoro-1H-indole-2-carbonyl) -4-propyl-piperidine-1 162 mg of -carboxylic acid tert-butyl ester were obtained as a white solid in 76% yield.

Step 5: (5- Fluoro -1H-indol-2-yl)-(4-propyl-piperidin-4-yl)- Methanone

162 mg of 4- (5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester are dissolved in 1M methanolic HCl and stirred at room temperature for 24 hours. It was. The solvent was removed to give an oil, which was precipitated from diethyl ether to give (5-fluoro-1H-indol-2-yl)-(4-propyl-piperidin-4-yl) -methanone; 132 mg of hydrochloride were obtained in 97% yield as a solid. MS = 289 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  18

(4-propyl-piperidin-4-yl) -quinolin-2-yl-methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme X below.

Scheme X

Step 1: 2- Iodoquinoline

2-iodoquinoline is described by Kimber, et. al. ( Tetrahedron 2000 , 56 , 3575). To a solution of 2-chloroquinoline (10.0 g, 61.5 mmol) in CH ₃ CN (100 mL) was added sodium iodide (14 g, 92.3 mmol) and acetyl chloride (8.8 mL, 123 mmol). The reaction mixture was stirred at 100 ° C. for 5 hours, then cooled to room temperature and quenched with 10% aqueous K ₂ CO ₃ (100 mL) and 5% aqueous NaHSO ₃ (50 mL). The aqueous layer was extracted twice with dichloromethane, then the combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% -20% EtOAc in hexanes) to give 9.7 g (70%) of 2-iodoquinoline as a yellow solid.

Step 2: 4- ( Hydroxy -Quinolin-2-yl- methyl ) -4-propyl-piperidine-1- Carboxylic acid  tert-butyl ester

Isopropyl magnesium chloride (2.0 M in THF, 1.6 mL, 3.2 mmol) was slowly added to a solution of 2-iodoquinoline (670 mg, 2.6 mmol) in THF (10 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 min, then slowly stirred a solution of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (670 mg, 2.6 mmol) in THF (3 mL). Added. The reaction mixture was stirred at 0 ° C. for 30 minutes, then warmed to room temperature, quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, MgSO ₄ Dried over, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% -20% EtOAc in hexanes) to 190 mg (19%) of 4- (hydroxyquinolin-2-yl-methyl) -4-propyl-piperidine-1 -Carboxylic acid tert-butyl ester was obtained as a yellow oil.

Step 3: 4-propyl-4- (quinoline-2- Carbonyl ) -Piperidine-1- Carboxylic acid tert -Butyl ester

Manganese (IV) in a solution of 4- (hydroxyquinolin-2-yl-methyl) -4-propyl-piperidine-1-carboxylic acid tert-butyl ester (190 mg, 0.5 mmol) in toluene (5 mL) Oxide (activated, 260 mg, 3.0 mmol) was added. The reaction mixture was heated at 100 ° C. for 3 hours and then cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated and purified by flash chromatography (0%-20% EtOAc in hexane) to 124 mg (67%) of 4-propyl-4- (quinoline-2-carbonyl) -piperidine-1-carboxylic acid tert-butyl ester was obtained as a colorless oil.

Step 4: (4-propyl-piperidin-4-yl) -quinolin-2-yl- Methanone

4-propyl-4- (quinoline-2-carbonyl) -piperidine-1-carboxylic acid tert-butyl ester (124 mg, 0.32 mmol) was dissolved in anhydrous 1.0M HCl solution in MeOH (5 mL). The reaction mixture was stirred at rt for 15 h and then concentrated under reduced pressure to afford 82 mg (80%) of (4-propyl-piperidin-4-yl) -quinolin-2-yl-methanone hydrochloride as a yellow solid Obtained as. MS = 283 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 19

[3- (3,3- Dimethyl -Butyl)- Pyrrolidine -3-yl]-(5- Fluoro - Benzo [b] thiophene -3-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme Y below.

Scheme Y

Step 1: 3- (3,3- Dimethyl -Butyl) -3-[(5- Fluoro - Benzo [b] thiophene -3 days)- Hyde Roxy methyl ]- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

A mixture of 3-bromo-5-fluoro-benzothiophene (0.4 g, 1.73 mmol), magnesium (0.051 g, 2.1 mmol) and several iodine particles in anhydrous tetrahydrofuran (10 ml) was refluxed for 7 hours. After cooling, it was cooled in an ice bath. To the reaction mixture was a solution of 3- (3,3-dimethyl-butyl) -3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.38 mmol) in anhydrous tetrahydrofuran (9 ml). Was added slowly. The reaction mixture was stirred at ice bath temperature for 1 hour and quenched with saturated aqueous ammonium chloride solution. The aqueous solution was extracted with ethyl acetate, which was washed with brine and dried over anhydrous sodium sulfate. After removal of the desiccant, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% ethyl acetate in hexane) to give 3- (3,3-dimethyl-butyl) -3-[(5-fluoro-benzo [b] thiophen-3 -Yl) -hydroxy-methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a yellow foam (0.13 g, 21%). MS = 436 [M + H] ⁺ .

Step 2: 3- (3,3- Dimethyl -Butyl) -3- (5- Fluoro - Benzo [b] thiophene -3- Carbonyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester

3- (3,3-dimethyl-butyl) -3- (5-fluoro-benzo [b] thiophene-3-carbonyl) -pyrrolidine-1-carboxylic acid tert-butyl ester, Example 18 3- (3,3-dimethyl-butyl) -3-[(5-fluoro-benzo [b] thiophen-3-yl) -hydroxy-methyl] -pyrroli using the procedure of step 3 in Prepared by oxidation with MnO ₂ from dine-1-carboxylic acid tert-butyl ester.

Step 3: [3- (3,3- Dimethyl -Butyl)- Pyrrolidine -3-yl]-(5- Fluoro - Benzo [b] thiophene -3 days)- Methanone

[3- (3,3-Dimethyl-butyl) -pyrrolidin-3-yl]-(5-fluoro-benzo [b] thiophen-3-yl) -methanone was used in the step of Example 18 3- (3,3-dimethyl-butyl) -3- (5-fluoro-benzo [b] thiophene-3-carbonyl) -pyrrolidine-1-carboxylic acid tert-butyl using the procedure of 4 Prepared from ester. MS = 334 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  20

(7-Fluoro-benzo [b] thiophen-2-yl)-[3- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme Z below.

Scheme Z

Step 1: 3-[(7- Fluoro - Benzo [b] thiophene -2 days)- Hydroxy - methyl ] -3- ( Tetraha Idro-pyran-4- Yl methyl ) - Pyrrolidine -One- Carboxylic acid tert -Butyl ester

To a solution of 7-fluoro-benzothiophene (0.22 g, 1.44 mmol) in anhydrous tetrahydrofuran (10 ml) at -78 ° C was added dropwise a solution of n-BuLi (1.6M, 0.9 ml, 1.44 mmol) in hexanes. It was. The reaction mixture was stirred at -78 ° C. for 1 hour and then 3-formyl-3- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert in anhydrous tetrahydrofuran (5 ml). A solution of butyl ester (0.3 g, 1.01 mmol) was added. The reaction mixture was stirred at −78 ° C. for 3 hours, quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-45% ethyl acetate in hexane) to give 3-[(7-fluoro-benzo [b] thiophen-2-yl) -hydroxy-methyl] -3- ( Tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a colorless semisolid (0.138 g, 30%). MS = 450 [M + H] ⁺ .

Step 2: 3- (7- Fluoro - Benzo [b] thiophene -2- Carbonyl ) -3- ( Tetrahydro Pyran-4-ylmethyl) Pyrrolidine -One- Carboxylic acid tert -Butyl ester

3- (7-fluoro-benzo [b] thiophene-2-carbonyl) -3- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester, 3-[(7-fluoro-benzo [b] thiophen-2-yl) -hydroxy-methyl] -3- (tetrahydro-pyran) by oxidation with MnO ₂ using the procedure of step 3 of 18 Prepared from -4-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 3: (7- Fluoro - Benzo [b] thiophene -2-yl)-[3- ( Tetrahydro -Pyran-4- Yl methyl ) - Pyrrolidine -3 days]- Methanone

(7-Fluoro-benzo [b] thiophen-2-yl)-[3- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -methanone of Example 18 3- (7-fluoro-benzo [b] thiophen-2-carbonyl) -3- (tetrahydro-pyran-4-ylmethyl) -pyrrolidine-1-carboxylic acid tert using the procedure of step 4 Prepared from -butyl ester. MS = 348 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example 21

(4-Chloro-5-methyl-thiophen-2-yl)-(3-propyl-pyrrolidin-3-yl) -methanone

The synthesis procedure described in this example was carried out according to the process shown in Scheme AA below.

Scheme AA

Step 1: 3-[(4,5- Dichloro -Thiophen-2-yl)- Hydroxy - methyl ] -3-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

3-[(4,5-Dichloro-thiophen-2-yl) -hydroxy-methyl] -3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester, the procedure of step 4 of Example 18 Was prepared from 2,3-dichloro-thiophene and 3-formyl-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 2: 3- (4,5- Dichloro -Thiophene-2- Carbonyl ) -3-propyl- Pyrrolidine -One- Carboxylic acid  tert-butyl ester

3-[(4,5-Dichloro-thiophen-2-yl) -hydroxy-methyl] -3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester in toluene (20 ml) (0.423 g, 1.07 mmol) and manganese (IV) oxide (1.3 g, 12.7 mmol) were refluxed for 2 hours and filtered through a pad of celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give 3- (4,5-dichloro-thiophen-2-carbonyl) -3-propyl-pyrrolidine-1-carboxylic acid tert- Butyl ester was obtained as a pale yellow solid (0.27 g, 64%). M + Na: 414.

Step 3: 3- (4- Chloro -5- methyl -Thiophene-2- Carbonyl ) -3-propyl- Pyrrolidine -One- Carboxylic acid tert -Butyl ester

3- (4,5-Dichloro-thiophene-2-carbonyl) -3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.512 mmol) in dioxane (10 ml), trimethyl A mixture of boroxine (0.24 g, 1.91 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.06 g, 0.051 mmol) was refluxed for 3 hours, Cool to room temperature. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give 3- (4-chloro-5-methyl-thiophen-2-carbonyl) -3-propyl-pyrrolidine-1-carboxylic acid tert -Butyl ester was obtained as a solid (0.166 g, 87%). M + Na: 394.

Step 4: (4- Chloro -5- methyl -Thiophen-2-yl)-(3-propyl- Pyrrolidine -3 days)- Methanone

3- (4-Chloro-5-methyl-thiophene-2-carbonyl) -3-propyl-pyrrolidine-1-carboxylic acid tert-butyl in a mixed solvent of methanol and dichloromethane (3 ml / 3 ml) To a solution of ester (0.16 g, 0.43 mmol) was added a solution of hydrochloric acid (1M, 10 ml) in anhydrous ether. The solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was triturated with hexane and diethyl ether to give (4-chloro-5-methyl-thiophen-2-yl)-(3-propyl-pyrrolidin-3-yl) -methanone hydrochloride as a solid (0.129 g, 97%). [M + H] ⁺ : 272

(4,5-Dichloro-thiophen-2-yl)-(3-propyl-pyrrolidin-3-yl) -methanone was prepared similarly by removing step 3. MS = 292 [M + H] ⁺ .

Additional compounds prepared by the above procedure are shown in Table 1.

Example  22

Pharmaceutical formulation

Pharmaceutical formulations for delivery by various routes are formulated as shown in the table below. As used in the table, "active ingredient" or "active compound" means one or more compounds of formula (I).

Compositions for Oral Administration

The ingredients were mixed and dispersed into capsules containing about 100 mg each. One capsule corresponds approximately to the total daily dose.

Compositions for Oral Administration

The components were combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) using an appropriate tablet machine.

Compositions for Oral Administration

The components were mixed to form a suspension for oral administration.

Parenteral  Formulation

The active ingredient was dissolved in some water for injection. Thereafter, a sufficient amount of sodium chloride was added with stirring to prepare an isotonic solution. The solution was weighed with the remaining water for injection, filtered through a 0.2 μm membrane filter and packaged under sterile conditions.

Suppository formulation

The components were melted together and mixed on a steam bath and then poured into a mold containing a total weight of 2.5 g.

Topical formulations

All components except water were combined and heated to about 60 ° C. with stirring. Thereafter, a sufficient amount of water was added with vigorous stirring at about 60 ° C. to emulsify the components, and then water was added to about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing about 0.025 to 0.5% active compound were prepared as nasal spray formulations. The formulation optionally contained inert ingredients such as microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and the like. Hydrochloric acid can be added to adjust the pH. Nasal spray formulations may typically be delivered via a nasal spray metering pump that carries about 50-100 μl of the formulation per actuation action. A typical dosing regimen is 2-4 sprays every 4-12 hours.

Example  23

Flash Proximity Analysis SPA Human serotonin using Transport ( hSERT ) Screening for Antagonists

The screening assay of this example was used to determine the affinity of the ligand in the hSERT transporter by competition with [ ³ H] -citalopram.

Scintillation Proximity Assay (SPA) is performed by stimulating the emission of light by bringing the radioligand very close to the scintillator of the beads. In this assay, the receptor-containing membrane was precoupled to the SPA beads and the amount of binding of the appropriate radioligand to the transporter was determined. Luminescence was proportional to the amount of radioligand bound. Unbound radioligand did not produce a signal as a result of being in close proximity to the scintillator (lack of energy transfer).

HEK-293 cells stably expressing recombinant hSERT (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258) were cultured in medium (10% FBS, 300 μg / ml G418 and 2 mM L- DMEM high glucose with glutamine) and incubated at 5% CO ₂ and 37 ° C. Cells were released from the culture flasks using PBS for 1-2 minutes. Cells were then centrifuged at 1000 g for 5 minutes and resuspended in PBS before being used for membrane preparation.

Cell membranes were prepared using 50 mM TRIS pH 7.4 membrane preparation buffer. Cell membranes were prepared from a single cube (total 7.5 × 10 ⁹ cells). Cells were homogenized using Polytron (media setting for 4 sec rupture). The homogenate was then centrifuged at 48,000 × g for 15 minutes, then the supernatant was removed and discarded, and the pellet was resuspended in fresh buffer. After the second centrifugation, the pellets were re-homogenized and brought to the final volume determined during the analysis. Typically, membrane sections were fractionated by 3 mg / ml (w: v) and stored at -80 ° C.

Scintillation Proximity For IC ₅₀ / Ki measurements, 50 mM Tris-HCl and 300 mM NaCl pH 7.4 buffer were used. Compounds of the present invention were diluted from 10 mM to 0.1 nM FAC (10 point curve, full log / half log dilution) via Beckman Biomek 2000 using a serial dilution protocol. Then, the test compound was transferred (20 μl / well) and [ ³ H] -citalopram radioligand was added at 50 μl / well. Membranes and beads were prepared at a ratio of 10 μg: 0.7 mg and 0.7 mg PVT-WGA Amersham beads (Cat # RPQ0282V) were added to each well. 130 μl of membrane: bead mixture was added to the assay plate. The mixture was allowed to stand at room temperature for 1 hour before Packard TopCount LCS, typical scintillation proximity counting protocol settings (energy range: low, efficiency mode: normal, zone A: 1.50-35.00, zone B: 1.50-) 256.00, counting time (minutes): 0.40, background subtraction: none, half-life correction: none, quench indicator: tSIS, platemap blank subtraction: none, crosstalk reduction: off).

The percent inhibition of each compound tested was calculated [(compound count per minute (CPM) -nonspecific CPM at maximum concentration) / total CPM * 100]. Activity Base / XLfit using Equation 1 was used to determine the concentration (IC ₅₀ ) producing 50% inhibition using an iterative nonlinear curve fitting technique:

Where

Max is the total join,

Minimal is nonspecific binding,

x is the concentration of the tested compound (M),

n is the Hill slope.

The inhibition dissociation constant (Ki) for each compound was determined according to the Cheng-Prusoff method and then converted to the negative logarithm of pKi (pKi).

Using the above procedure, the compounds of the present invention were found to have affinity for human serotonin transporters. For example, naphthalen-2-yl- (3-propyl-pyrrolidin-3-yl) -methanone showed a pKi of approximately 9.82 in this assay.

Example  24

Flash Proximity Analysis SPA Human norepinephrine with On the transport (hNET)  Screening for Compound Activity

This assay was used to determine the affinity of the ligand for the hNET transporter by competition with [ ³ H] -nisoxetine. As in the hSERT assay of the above example, the receptor-containing membrane was precoupled to the SPA beads and the amount of binding of the appropriate radioligand to the transporter was determined. Luminescence was proportional to the amount of radioligand bound and unbound radioligand produced no signal.

HEK-293 cells stably expressing recombinant hNET (clone: HEK-hNET # 2) (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258) were cultured in medium (10% FBS, DMEM high glucose with 300 μg / ml G418 and 2 mM L-glutamine) and incubated at 5% CO ₂ and 37 ° C. Cells were released from the culture flasks using PBS for 1-2 minutes. Cells were then centrifuged at 1000 g for 5 minutes and resuspended in PBS before being used for membrane preparation.

Cell membranes were prepared using 50 mM TRIS pH 7.4 membrane preparation buffer. Cell membranes were prepared from a single cube (total 7.5 × 10 ⁹ cells). Cells were homogenized using polytron (media setting for 4 sec rupture). The homogenate was then centrifuged at 48,000 × g for 15 minutes, then the supernatant was removed and discarded, and the pellet was resuspended in fresh buffer. After the second centrifugation, the pellets were re-homogenized and brought to the final volume determined during the analysis. Typically, the membrane fractions are fractionated by 3-6 mg / ml (w: v) and stored at -80 ° C.

For scintillation proximity assay IC ₅₀ / Ki measurements, ³ [H] nisoxetine radioligand (Amersham Cat. # TRK942 or Perkin Elmer Cat # NET1084, inactive: 70-87 Ci / mmol, storage concentration: 1.22 e-5M, final concentration: 8.25e-9M), and 50 mM Tris-HCl, 300 mM NaCl (pH 7.4) buffer were used. Compounds of the invention were diluted from 10 mM to 0.1 nM FAC (10 point curve, full log / half log dilution) via Beckman Biomex 2000 using a serial dilution protocol. The test compound was then transferred (20 μl / well) and radioligand was added at 50 μl / well. Membranes and beads were prepared at a ratio of 10 μg: 0.7 mg and 0.7 mg PVT-WGA Amersham beads (Cat # RPQ0282V) were added to each well. 130 μl of membrane: bead mixture was added to the assay plate. The mixture was allowed to stand at room temperature for 1 hour before packard top count LCS, typical SPA counting protocol settings (energy range: low, efficiency mode: normal, area A: 1.50-35.00, area B: 1.50-256.00, counting time (minutes) ): 0.40, background sensitivity: none, half-life correction: none, quench indicator: tSIS, platemap blank sensitivity: none, crosstalk reduction: off).

The percent inhibition was calculated for each compound tested [(Compound CPM-nonspecific CPM at maximum concentration) / Total CPM * 100]. Activity base / XLfit using Equation 1 was used to determine the concentration (IC ₅₀ ) that produces 50% inhibition using an iterative nonlinear curve fitting technique:

Equation 1

Where

Max is the total join,

Minimal is nonspecific binding,

x is the concentration of the tested compound (M),

n is the heel slope.

The inhibitory dissociation constant (Ki) for each compound was converted to the negative logarithm of Ki (pKi) after determination according to the V-Prusov method.

Using the above procedure, the compounds of the present invention were found to have affinity for human norepinephrine transporters. For example, (7-fluoro-1H-indol-5-yl)-[(S) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone is approximately PKi of 9.2 is shown.

Example  25

Flash Proximity Analysis SPA Human dopamine with On transport  Screening for Compound Activity

This assay was used to determine the affinity of the ligand for the dopamine transporter by competition with [ ³ H] -banoxerine.

HEK-293 cells stably expressing recombinant hDAT (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258) were cultured in medium (10% FBS, 300 μg / ml G418 and 2 mM L−). DMEM with glutamine high glucose) and keep 5% CO ₂ And incubated at 37 ° C. Prior to the experiment, cells were plated for 4 hours by placing approximately 30,000 cells per well (in PBS) on a white opaque Cell-Tak coated 96 well plate. Extra buffer was apriate from the cell plate using an ELx405 plate washer.

For scintillation proximity assay IC ₅₀ / Ki measurements, ³ [H] banoxerine (GBR 12909) radioligand, inactive approximately 59 Ci / mmol, storage concentration, 400 nM, and 50 mM Tris-HCl, 300 mM NaCl (pH 7.4) buffer Used. Compounds of the invention were diluted from 10 mM to 0.1 nM FAC (10 point curve, full log / half log dilution) via Beckman Biomex 2000 using a 10-point dilution protocol. The mixture was allowed to stand at room temperature for 30 minutes before packard top count LCS, typical scintillation proximity counting protocol settings (counting time in minutes: 0.40, background sensitivity: none, half-life correction: none, quench indicator: tSIS, platemap blank Sensitization: none, crosstalk reduction: off).

The percent inhibition of each compound tested was calculated [(compound CPM-nonspecific CPM at maximum concentration) / total CPM * 100]. Activity base / XLfit using Equation 1 was used to determine the concentration (IC ₅₀ ) that produces 50% inhibition using an iterative nonlinear curve fitting technique:

Equation 1

Where

Max is the total join,

Minimal is nonspecific binding,

x is the concentration of the tested compound (M),

n is the heel slope.

Inhibition dissociation constants (Ki) for each compound were converted to the negative logarithm of Ki (pKi) after it was determined according to the V-Prusov method.

Using the above procedure, the compounds of the present invention were found to have affinity for human dopamine transporters. For example, [(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl]-(7-fluoro-1H-indol-5-yl) -methanone is The assay showed a pKi of approximately 9.2.

Example  26

Formalin Pain Assay

Male Sprague Toray rats (180-220 g) are placed in individual Plexiglas cylinders and allowed to familiarize themselves with the test environment for 30 minutes. An excipient, drug or positive control (morphine 2 mg / kg) is administered subcutaneously at 5 ml / kg. 15 minutes after dosing, formalin (50 μl, 5%) is injected into the flat surface of the right hind paw using a 26 gauge needle. The rats are soon returned to the observation chamber. Mirrors located around the chamber allow unobstructed observation of the formalin-infused foot. The blind observer records the duration of the nociphensive behavior of each animal using an automatic behavior timer. Hind foot licking and shaking / lifting were recorded separately for 5 minutes for a total of 60 minutes. The sum of the seconds spent licking or shaking from the 0th minute to the 5th minute is considered the initial phase, and the sum of the seconds spent licking or shaking the 15th to 40th minute is considered the late phase. Collect serum samples.

Example  27

Colon Pain Assay

Adult male Sprague-Toray rats (350-425 g; Harlan, Indianapolis, Indiana) were housed 1-2 animals per cage in animal care facilities. Rats were deeply anesthetized with pentobarbital sodium (45 mg / kg) administered intraperitoneally. Electrodes were placed and fixed in external oblique muscle tissue for EMG recording. Tunnel the electrode leads subcutaneously and out of the body from the nape for later access. After surgery, rats were individually housed and allowed to recover for 4-5 days before testing.

The downward colon and rectum are inflated by pressure-controlled inflation of a 7-8 cm long flexible latex balloon tied around the flexible tube. The balloon is lubricated, inserted into the colon through the anus, and secured by tape wrapping a balloon catheter at the base of the tail. Colorectal dilatation (CRD) is obtained by opening the solenoid gate to a constant pressure air reservoir. The colonic pressure is regulated by a pressure regulator and continuously monitored. The response is quantified as Visceral Motor Response (VMR), a contraction of abdominal and hind limb muscle tissue. EMG activity produced by contraction of external oblique muscle tissue is quantified using Spike2 software (Cambridge Electronic Design). Each expansion attempt lasts 60 seconds and EMG activity is quantified for 20 seconds before expansion (baseline), during 20 seconds expansion and 20 seconds after expansion. The increase in the total number of times recorded above the baseline during expansion is defined as the response. Stable baseline responses to CRD (10, 20, 40 and 80 mmHg, 20 seconds, 4 minute intervals) are obtained in conscious, unsedated rats prior to any treatment.

Response to early colon dilatation in the colonic hypersensitivity model and acute visceral pain model produced by intracolonical treatment with colonic dipped zymoic acid (1 mL, 25 mg / ml) using a gavage syringe inserted at a depth of about 6 cm. Compounds are evaluated for their effects.

Acute visceral pain: to test the effect of the drug on acute visceral pain, after the baseline response is established, one of three drugs, excipients or positive controls (morphine, 2.5 mg / kg) is administered; The reaction to expansion occurs for the next 60 to 90 minutes.

Visceral hypersensitivity: Intracolonial treatment, followed by intra-crystal treatment after baseline response is established, to test the effect of the drug or excipient. Prior to drug testing at 4 hours, the response to swelling is assessed to establish the presence of hypersensitivity. In zymosan-treated rats, one of three drugs, excipients or three positive controls (morphine, 2.5 mg / kg) is administered 4 hours after treatment with zymoic acid, and the response to swelling occurs for the next 60 to 90 minutes.

Example  28

Sciatic Nerve Damaged Chronic Compression In the rat  cold Allodynia

A chronic contractile injury (CCI) model of neuropathic pain in rats is used to determine the effect of the compounds of the present invention on cold allodynia, where the cold allodynia is a metal-plate bottom, 1.5-2.0 cm deep and 3-4 ° C. It is measured in a cold water bath with water (Gogas, KR et. Al., Analgesia, 1997, 3, 1-8).

Specifically, anesthetize CCI rats; Three branches of the sciatic nerve are placed and four sutures (4-0 or 5-0 chromed guts) are circumferentially around the sciatic nerve closest to the three branches. The rat is then left to recover from the surgery. On days 4-7 after surgery, first place the rats individually in a cold water bath to record the total number of injured paws lifted (damaged paws lifted out of the water) for a period of one minute to cold-induced allodynia. Rats are evaluated. Feet lifts associated with moving or changing body positions are not recorded. Rats that display at least 5 lifts per minute 4-7 days after surgery are considered to exhibit cold allodynia and are used in subsequent studies. In acute studies, excipients, reference compounds or compounds of the present invention are administered subcutaneously 30 minutes prior to testing. The effect of repeated administration of a compound of the invention on cold allodynia is measured 14, 20 or 38 hours after the last oral administration according to the following dosing regimen: excipient, reference compound or present at intervals of about 12 hours (BID) for 7 days. Administration of the Compounds of the Invention.

While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various modifications may be made and equivalents may be substituted without departing from the true scope and scope of the invention. In addition, various modifications may be made to adapt a particular situation, the composition of a substance, a component, a method of manufacture, or a method of manufacture to an objective scope and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims (11)

A compound of formula (I)
(I)

Where
R ¹ is 4-chloro-3-methyl-phenyl;
2-amino-3,4-dichloro-phenyl;
3,4-dichloro-phenyl;
4-chloro-3- (3,3-dimethyl-butoxy) -phenyl;
3-benzyloxy-4-chloro-phenyl;
7-fluoro-1 H -indol-5-yl;
4-amino-3-chloro-5-trifluoromethyl-phenyl;
4-chloro-3- (4-fluoro-phenoxy) -phenyl;
4-chloro-3- (2-fluoro-phenoxy) -phenyl;
3-benzyloxy-4-chloro-phenyl;
4-chloro-3- (3,3-dimethyl-butoxy) -phenyl;
4-chloro-2-phenoxy-phenyl;
4-chloro-3- (tetrahydro-pyran-4-ylmethoxy) -phenyl;
4-chloro-3-trifluoromethoxy-phenyl;
4-chloro-3-phenylsulfanyl-phenyl;
3-benzenesulfonyl-4-chloro-phenyl;
4-chloro-3- (2-fluoro-phenoxy) -phenyl;
4-chloro-3- (4-fluoro-phenoxy) -phenyl;
4-chloro-3-phenoxy-phenyl;
4-bromo-3-phenoxy-phenyl;
4-amino-3-chloro-5-fluoro-phenyl;
4-amino-3-chloro-phenyl;
4-chloro-3- (4-trifluoromethyl-phenoxy) -phenyl;
3-chloro-4-methyl-phenyl;
Naphthalen-2-yl;
4-chloro-2-phenoxy-phenyl;
Phenyl;
3-chloro-4-methylamino-phenyl;
4-chloro-3-phenoxy-phenyl;
4-chloro-3- ( 2H -pyrazol-3-yl) -phenyl;
4-chloro-3- (methyl-phenyl-amino) -phenyl;
1 H -indol-5-yl;
4-chloro-3-pyridin-3-yl-phenyl;
3-bromo-4-imidazol-1-yl-phenyl; or
4-chloro-3-imidazol-1-yl-phenyl;
R ² is 3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;
(R) -3-isobutyl-pyrrolidin-3-yl;
(1R, 2S, 4S) -2-Butyl-7-aza-bicyclo [2.2.1] hept-2-yl;
3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl;
3-propyl-pyrrolidin-3-yl;
3-isobutyl-pyrrolidin-3-yl;
3-ethyl-pyrrolidin-3-yl;
(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl;
(S) -3- (3-methyl-butyl) -pyrrolidin-3-yl;
(S) -3-isobutyl-pyrrolidin-3-yl;
(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;
(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl;
(S) -3-propyl-pyrrolidin-3-yl;
(R) -3-propyl-pyrrolidin-3-yl;
(R) -2-propyl-pyrrolidin-2-yl) -methanone;
4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl;
4-isobutyl-piperidin-4-yl;
4-propyl-piperidin-4-yl;
4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl;
4- (3-methyl-butyl) -piperidin-4-yl;
4-cyclopentylmethyl-piperidin-4-yl;
4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl;
4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl;
4- (3,4-Dichloro-benzyl) -piperidin-4-yl;
(1R, 2S, 5R) -2-Isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl;
(1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl;
(1R, 2S, 5R) -2-Ethyl-8-aza-bicyclo [3.2.1] oct-2-yl;
3-propyl-piperidin-3-yl;
(1R, 2R, 5R) -2-propyl-8-aza-bicyclo [3.2.1] oct-2-yl;
(1R, 2R, 5R) -2-Ethyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl;
(1R, 2R, 5R) -2-Butyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl;
3- (3,3-dimethyl-butyl) -piperidin-3-yl;
(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl; or
(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;
The compound is selected from the group consisting of the following compounds:
(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
((1R, 2S, 4S) -2-Butyl-7-aza-bicyclo [2.2.1] hept-2-yl)-(3,4-dichloro-phenyl) -methanone;
[4-Chloro-3- (3,3-dimethyl-butoxy) -phenyl]-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(3-benzyloxy-4-chloro-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-trifluoromethyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-[3- (3, 3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(3-benzyloxy-4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (3,3-dimethyl-butoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-chloro-2-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (tetrahydro-pyran-4-ylmethoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenylsulfanyl-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(3-benzenesulfonyl-4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-chloro-3-phenoxy-phenyl)-(3-ethyl-pyrrolidin-3-yl) -methanone;
(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (4-trifluoromethyl-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;
(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;
(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;
(4-Chloro-2-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;
[4- (3,4-Dichloro-benzyl) -piperidin-4-yl] -phenyl-methanone;
(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;
[4-Chloro-3- (methyl-phenyl-amino) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;
( 1H -Indol-5-yl)-((1R, 2R, 5R) -2-propyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
((1R, 2R, 5R) -2-butyl-8-methyl-8-aza-bicyclo [3.2.1] oct-2-yl)-(3,4-dichloro-phenyl) -methanone;
(4-Chloro-3-pyridin-3-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;
(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;
(3-bromo-4-imidazol-1-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;
(4-chloro-3-imidazol-1-yl-phenyl)-(3-propyl-piperidin-3-yl) -methanone;
(3,4-Dichloro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone; And
(3,4-Dichloro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone. The method of claim 1,
Wherein said compound is selected from the group consisting of:
(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;
(4-chloro-2-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (2-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
[4-Chloro-3- (4-fluoro-phenoxy) -phenyl]-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-chloro-3-phenoxy-phenyl)-(3-ethyl-pyrrolidin-3-yl) -methanone;
(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;
(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;
(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;
(4-Chloro-2-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone;
(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone;
(3,4-Dichloro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone; And
(3,4-Dichloro-phenyl)-[(R) -3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone. The method of claim 1,
Wherein said compound is selected from the group consisting of:
(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(2-amino-3,4-dichloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;
(4-chloro-3-trifluoromethoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-bromo-3-phenoxy-phenyl)-(3-propyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-phenyl)-((R) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((R) -2-propyl-pyrrolidin-2-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;
(3-Chloro-4-methyl-phenyl)-[4- (3-methyl-butyl) -piperidin-4-yl] -methanone;
(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methylamino-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2S, 5R) -2-isobutyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
(3,4-Dichloro-phenyl)-((1R, 2R, 5R) -2-ethyl-8-aza-bicyclo [3.2.1] oct-2-yl) -methanone;
[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone; And
(3,4-Dichloro-phenyl)-[3- (3,3-dimethyl-butyl) -piperidin-3-yl] -methanone. The method of claim 1,
Wherein said compound is selected from the group consisting of:
(4-Chloro-3-methyl-phenyl)-[3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(7-Fluoro-1 H -indol-5-yl)-[3- (2-methoxy-2-methyl-propyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(R) -3- (3-methyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-amino-3-chloro-5-fluoro-phenyl)-[(S) -3- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -methanone;
(4-amino-3-chloro-phenyl)-((S) -3-isobutyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-((S) -3-propyl-pyrrolidin-3-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(3-isobutyl-pyrrolidin-3-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (1-methyl-cyclopropylmethyl) -piperidin-4-yl] -methanone;
(3-chloro-4-methyl-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
Naphthalen-2-yl- (4-propyl-piperidin-4-yl) -methanone;
(3,4-Dichloro-phenyl)-[4- (2-methoxy-2-methyl-propyl) -piperidin-4-yl] -methanone;
(4-cyclopentylmethyl-piperidin-4-yl)-(3,4-dichloro-phenyl) -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-pyran-4-ylmethyl) -piperidin-4-yl] -methanone;
(3,4-Dichloro-phenyl)-[4- (tetrahydro-furan-2-ylmethyl) -piperidin-4-yl] -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-isobutyl-piperidin-4-yl) -methanone;
(4-Chloro-3-phenoxy-phenyl)-(4-propyl-piperidin-4-yl) -methanone; And
[4-Chloro-3- ( 2H -pyrazol-3-yl) -phenyl]-(3-propyl-piperidin-3-yl) -methanone. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier and / or adjuvant. The method according to any one of claims 1 to 4,
Compounds for use as therapeutically active substances. The method according to any one of claims 1 to 4,
A compound for use as a therapeutically active substance for the treatment or prevention of diseases associated with monoamine reuptake inhibition. A method of treating or preventing a disease associated with monoamine reuptake inhibition, in particular depression and / or anxiety, comprising administering an effective amount of a compound of any one of claims 1 to 4 to a subject in need thereof. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment or prevention of diseases associated with monoamine reuptake inhibition. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament useful for the treatment or prevention of depression and / or anxiety. Inventions described herein.